JP5274455B2 - Prinone derivatives as HM74A agonists - Google Patents

Description

  This application is filed with US Provisional Patent Application No. 60 / 815,935, filed June 23, 2006, and US Provisional Patent Application No. 60 / 922,924, filed April 11, 2007, each of which is incorporated herein in its entirety. Insist on the benefit of priority over

  The present invention relates to agonists of the HM74a receptor, compositions thereof and methods of their use.

  Coronary artery disease (or CAD) is the first cause of death in the United States (Non-patent Document 1). The onset and progression of CAD involves a complex interaction between multiple physiological processes, including inflammation, lipid homeostasis, and insulin resistance / diabetes. Several clinical studies are now due to the tendency of three major components of plasma lipids, low density lipoprotein (or LDL), high density lipoprotein (or HDL) and triglyceride (TG) to develop atherosclerosis and CAD Is involved. Increased plasma LDL and / or TG-rich lipoproteins and plasma HDL levels alongside other risk factors such as positive family history of CAD, increased body mass index, hypertension and insulin resistance / diabetes Is defined as a major cardiovascular risk factor by Non-Patent Document 2. Therefore, therapeutic treatments designed to impact these plasma lipid components in addition to those underlying insulin resistance are of great interest to medical organizations.

  In terms of LDL reduction, the statin class of drugs is structurally similar to the molecule hydroxymethylglutaryl-coenzyme A (HMG-CoA), a precursor of cholesterol biosynthesis. These drugs are competitive inhibitors of the rate limiting process of cholesterol biosynthesis catalyzed by HMG-CoA reductase. Mechanistically, statins lower LDL by upregulating LDL receptors in the liver, in addition to reducing the release of LDL into the circulation. As monotherapy, statin class lipid lowering agents can reduce plasma LDL levels by 30-60%, triglycerides by 25%, reduce the incidence of CAD by 25-60%, and reduce the risk of death by 30%. Statins have no appreciable effect on HDL. A mechanistically distinct drug, Ezetimbe (Zetia, Merck and Co.), also has the ability to lower plasma LDL, but functions by inhibiting cholesterol absorption by the small intestine by antagonism of the NPC1L1 receptor (Non-Patent Document 3 ). Monotherapy with Ezetimibe typically reduces LDL by 20%, but the maximum reduction is over 60% when co-formulated with statins. However, like statins, Ezetimibe has very little effect on plasma HDL.

  Statins may have a mild effect on circulating triglycerides, but PPAR alpha agonists (or fibrates) are much better at targeting this lipid endpoint. Fibrates function by increasing lipolysis and removal of triglyceride rich particles from plasma by activating lipoprotein lipase and decreasing the production of apolipoprotein C-III, an inhibitor of lipoprotein lipase activity To do. One such fibrate, Fenofibrate (Tricor, Abbott), has been shown in clinical studies to lower plasma triglyceride levels by 40-60%. Interestingly, the fibrate class of lipid-lowering agents also has a modest but significant effect on both LDL (20% reduction) and HDL (10% increase).

Currently, statin class LDL-lowering agents remain essential for the treatment of dyslipidemia. Despite the substantial reduction in cardiovascular cases achieved with this therapeutic approach, the cardio-protection provided to patients by these treatments remains incomplete. It is now clear that treatment aimed at increasing HDL cholesterol is important in terms of maximizing patient cardioprotection. The only treatments available to date that have the ability to effectively increase circulating levels of cardioprotective HDL and thus improve the progression of atherosclerosis in CAD patients are nicotinic acid (niacin or vitamin B ₃ ). Nicotinic acid was first reported in 1955 to modify the lipoprotein profile (Non-Patent Document 4). The effect is the broadest spectrum of all available treatments, and in addition to reducing circulating plasma LDL (16%) and triglycerides (38%), HDL levels (20-30%) are effective To rise. The clinical significance of this broad spectrum of activity has been demonstrated in several large clinical studies. In a recent ARBITER 2 study, patients treated with statins were randomized to either placebo or 1000 mg extended release (ER) niacin (Niaspan, Kos Pharmaceuticals). Patients receiving niacin showed a statistically significant reduction in carotid intima-media thickness and effective surrogate cardiovascular endpoint. This study also revealed a significant reduction in the rate of progression of intima-media thickening in subjects without detectable insulin resistance. This study demonstrates the incomplete cardioprotection afforded by statin therapy and demonstrates the utility of nicotinic acid in reducing the overall heart risk in patients with low HDL.

Although nicotinic acid has been used clinically for over 40 years to modify lipid profiles, the mechanism of action of the compound remains largely opaque. It has long been known that acute nicotinic acid dosing results in a serious reduction in circulating free fatty acids (FFA). This anti-lipolytic activity was first observed in 1980 in a membrane receptor associated with a decrease in intracellular cAMP (cyclic AMP, or cyclic adenosine monophosphate, or 3′-5′-cyclic adenosine monophosphate) levels. Is assumed to intervene (Non-Patent Document 6). This hypothesis was later confirmed and the implied G _{i / o} GPCR binding was verified using a pertussis susceptibility study (7). Identification of specific nicotinic acid binding sites on the surface of fat and spleen cells confirmed the membrane hypothesis, and using today's techniques, the G-protein binding of the receptor itself was purified (Non-Patent Document 8). This G-protein mediated antilipolytic activity of nicotinic acid has been used for 20 years to identify and characterize nicotinic acid analogs in terms of their therapeutic potential. Finally, in 2003, two independent groups simultaneously published the cloning of an isolated Gi / o binding GPCR, HM74a, that binds nicotinic acid with high affinity (Non-patent Document 9). As asserted, this receptor has been shown to be expressed in adipose tissue and spleen and not only to nicotinic acid but also to structurally related derivatives previously shown to exhibit adipocyte antilipolytic activity. Join. Mice deficient in the HM74a rodent ortholog (Puma-g) by homologous recombination are resistant to nicotinic acid-dependent FFA reduction and TG reduction. Currently, it is hypothesized that nicotinic acid antilipolytic activity is based on this high affinity GPCR (HM74a), resulting in a decrease in intracellular cAMP followed by a decrease in hormone sensitive lipase (HSL) activity. Reduction in adipocyte lipolysis yields a decrease in circulating FFA and a corresponding decrease in liver TG, very low density LDL (VLDL) and LDL. The increase in the level of HDL results from an effective decrease in cholesterol ester transfer protein activity due to a decrease in the availability of VLDL acceptor molecules.

  In addition to impacting lipid levels and lipoprotein profiles, FFA plays a fundamental role in the regulation of glycemic control. It is now recognized that chronically elevated plasma FFA concentrations produce insulin resistance in muscle and liver and impair insulin secretion (reviewed in Non-Patent Document 10). In muscle, a sharp rise in plasma FFA concentration can increase muscle intracellular lipid content; this may have a direct negative effect on insulin receptor signaling and glucose transport. In the liver, elevated plasma FFA leads to accelerated lipid oxidation and acetyl-CoA deposition, the latter stimulating the rate-limiting process of hepatic glucose production. In the pancreas, prolonged exposure to elevated FFA has been shown to impair the ability of beta cells to secrete insulin in response to glucose. This data drives the hypothesis that adipose tissue FFA release is the primary driver of the underlying pathology in type 2 diabetes, and was designed to reduce FFA, for example by agonizing HM74A. The strategy may prove to be effective in improving insulin sensitivity and lowering blood glucose levels in patients with type 2 diabetes / metabolic syndrome.

The usefulness of nicotinic acid as a hypolipidemic / FFA-lowering agent is currently limited by four main factors. First, significant dosing of nicotinic acid is required to impact FFA release and improve lipid parameters. Immediate release (IR) nicotinic acid is often administered at 3-9 g / day to achieve efficacy, and ER nicotinic acid (Niaspan) is typically administered at 1-2 g / day. These high doses are determinative of the second problem with nicotinic acid therapy, hepatotoxicity. One of the major metabolic pathways of nicotinic acid is the formation of nicotinamide (NAM). Increased levels of NAM have been associated with increased liver transaminase, which can lead to liver failure. This toxicity is particularly problematic for sustained release formulations, which necessitates monitoring of liver enzymes during the onset of treatment. Third, high doses of nicotinic acid are associated with severe prostaglandin mediated skin flushing. Virtually all patients experience flushing when IR-nicotinic acid is administered at or near the T _max of the drug, and treatment interruption occurs in 20-50% of individuals. Although Niaspan shows an increase in dissolution time, it still has a flush frequency of about 70%, despite the recommended regimen that includes taking Niaspan with aspirin after a low-fat snack. . Fourth, nicotinic acid therapy often results in FFA rebound, a condition whereby fatty acid levels are not moderately suppressed throughout the dosage regimen, resulting in a compensatory increase in adipose tissue lipolysis. With immediate release nicotinic acid therapy, this rebound phenomenon is very significant and the daily FFA AUC increases rapidly after treatment. Such FFA excretion may lead to impaired glycemic control and elevated blood glucose levels, both of which have been shown to occur after nicotinic acid therapy in some individuals.

Nature Med 2002, 8: 1209-1262 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; Am J Cardio 2003, 92: 19i-26i) PNAS 2005, 102: 8132-8137 Altschul et al. Arch Biochem Biophys 1955, 54: 558-559 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2; Taylor et al. Circulation 2004, 110: 3512-3517 Aktories et al. FEBS Letters 1980, 115: 11-14 Aktories et al. FEBS Letters 1983, 156: 88-92 Lorenzen et al. Mol Pharm 2001, 59: 349-357 Wise et al. J Biol Chem 2003, 278: 9869-9874; Tunaru et al. Nat Med 2003, 9: 352-355 Defronzo et al. Int. J. Clin. Prac. 2004, 58: 9-21

  Given the importance and limitations of nicotinic acid in the regulation (particularly agonization) of the HM74a receptor, new small molecules designed to mimic the mechanism of action of nicotinic acid on HM74a have side effects such as hepatotoxicity. And offers the potential to achieve higher HDL, LDL, TG and FFA efficacy while avoiding skin flushing. Such treatments have a significant impact, including dyslipidemia, as well as insulin resistance, hyperglycemia and related syndromes, due to their ability to more moderately reduce plasma FFA levels during dosing intervals It is assumed. The present invention addresses these important objectives in addition to others.

The present invention includes, inter alia, compounds of formula I, wherein the constituent members are defined herein,
Or a pharmaceutically acceptable salt or prodrug thereof.

  The present invention further provides compositions comprising a compound of the present invention and at least one pharmaceutically acceptable carrier.

  The present invention further provides methods for modulating the HM74a receptor with the compounds of the present invention.

  The present invention further provides a method for agonizing the HM74a receptor by contacting the HM74a receptor with a compound of the present invention.

  The present invention further provides a method of treating a disease associated with the HM74a receptor.

  The present invention further provides a compound of the present invention for use in therapy.

  The present invention further provides a compound of the invention for use in the preparation of a medicament for use in therapy.

The present invention provides, inter alia, compounds that are agonists or partial agonists of HM74a and are useful in the treatment of various diseases, such as cardiovascular diseases. These compounds have the formula I,
Or a pharmaceutically acceptable salt or prodrug thereof, wherein
The dashed line indicates any bond;
X is N, CR ^3a , CR ^4a R ^5a or NR ^6a ;
Y is N, CR ^3b , CR ^4b R ^5b or NR ^6b ;
L is optionally substituted by 1, 2, 3, 4 or 5 R ^L1 ,-(C _1-6 alkylene)-(Q ¹ ) _m- (C _1-6 alkylene) _p- (Q ² ) _q- (C _1-6 alkylene) _r- where m and q are both 1 and p is 1;
R ¹ is H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or Cy, wherein the C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl is 1, Optionally substituted with 2, 3, 4 or 5 R ^L2 ;
R ² is halo, cyano, C ₁ haloalkyl or acetylenyl, where the acetylenyl is C _1-6 alkyl, C _2-6 alkenyl, C _2-10 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl Optionally substituted with a substituent selected from C _1-6 cyanoalkyl, Cy ⁴ , CN, NO ₂ , C (O) R ^b6 , C (O) NR ^c6 R ^d6 or C (O) OR ^a6 ;
R ^3a and R ^3b are H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ¹ , CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^{d , NR c R d, NR c} C (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR c R d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d , wherein the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl is Cy ¹ , CN, NO ₂ , halo, OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^{c C (O) R b,} NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR c R d, S (O) 2 R optionally substituted with 1, 2 or 3 substituents independently selected from ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d ;
R ^4a , R ^4b , R ^5a and R ^5b are H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1- 6} cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC ( ^{O) NR c1 R d1, NR} c1 R d1, NR c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, S (O) R b1, S ( O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 , wherein the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are Cy ² , CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC ( O) R ^b1, OC (O ^{NR c1 R d1, NR c1 R} d1, NR c1 C (O) R b1, NR c1 C (O) NR c1 R d1, NR c1 C (O) OR a1, S (O) R b1, S (O) Optionally substituted with 1, 2 or 3 substituents independently selected from NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 Is;
R ^6a and R ^6b are H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, Cy ² , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R independently selected from ^d1 , wherein the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are Cy ² , CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C ^{(O) NR c1 R d1,} C (O) OR a1, OC (O) R b1, OC (O) NR c1 R d1, NR c1 R d1, NR c1 C (O) R b1, NR c1 C (O ^{) NR c1 R d1, NR c1} C (O) oR a1, S (O) R b1, S (O) NR c1 R d1, S (O) 2 R b1, NR c1 S (O) 2 R b1 , and S It is independently selected from (O) ₂ NR ^c1 R ^d1 , Optionally substituted with 2 or 3 substituents;
R ^L1 and R ^L2 are halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O) R ^b2 , C (O) NR ^c2 R ^d2 , C (O) OR ^a2 , OC (O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C ( ^{O) NR c2 R d2, NR} c2 C (O) oR a2, S (O) R b2, S (O) NR c2 R d2, S (O) 2 R b2, NR c2 S (O) 2 R b2 and Independently selected from S (O) ₂ NR ^c2 R ^d2 ;
Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O) R ^b3 , C (O ^{) NR c3 R d3, C (} O) OR a3, OC (O) R b3, OC (O) NR c3 R d3, NR c3 R d3, NR c3 C (O) R b3, NR c3 C (O) OR ^{a3, S (O) R b3} , S (O) NR c3 R d3, S (O) 2 R b3 and S (O) ₂ NR ^c3 1,2,3,4 or 5 is selected from R ^d3 are independently Selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by a substituent of
Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , CN, NO ₂ , OR ^a4. , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 , C (O) OR ^a4 , OC (O) R ^b4 , OC (O) NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 From C (O) R ^b4 , NR ^c4 C (O) OR ^a4 , S (O) R ^b4 , S (O) NR ^c4 R ^d4 , S (O) ₂ R ^b4 and S (O) ₂ NR ^c4 R ^d4 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 independently selected substituents;
Cy ³ and Cy ⁴ are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO ₂ , OR ^a6 , SR ^a6 , C (O) R ^b6 , C (O) NR ^c6 R ^d6 , C (O) OR ^a6 , OC (O) R ^b6 , OC (O) NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C (O) R ^b6 , NR ^c6 C (O) OR ^a6 , S (O) R ^b6 , S (O) NR ^c6 R ^d6 , S (O) ₂ R ^b6 and S (O) ₂ NR ^c6 R independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from ^d6 ;
Q ¹ and Q ² are O, S, NH, CH ₂ , CO, CS, SO, SO ₂ , OCH ₂ , SCH ₂ , NHCH ₂ , CH ₂ CH ₂ , COCH ₂ , CONH, COO, SOCH ₂ , SONH, Independently selected from SO ₂ CH ₂ and SO ₂ NH;
R ^a and R ^a1 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ₂ , wherein the C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 1,2,3,4 selected from R ^d5 are independently Properly it is optionally substituted with five substituents;
R ^a2 , R ^a3 , R ^a4 , R ^a5 and R ^a6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Independently selected from cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are OH, cyano, amino, halo, C1-6 alkyl, aryl, arylalkyl, heteroaryl, Heteroarylalkyl, cycloalkyl or Optionally substituted with heterocycloalkyl;
R ^b and R ^b1 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein the C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 1,2,3,4 selected from R ^d5 are independently Properly it is optionally substituted with five substituents;
R ^b2 , R ^b3 , R ^b4 , R ^b5 and R ^b6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Independently selected from cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl , Heteroarylalkyl, cycloalkyl or hete Optionally substituted cycloalkyl;
R ^c and R ^d are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein the C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^b5 , OC (O) NR ^c5 R ^d5 , NR ^c5 R ^d5 , NR ^c5 C (O) R ^b5 , NR ^c5 C (O) NR ^c5 R ^d5 , NR ^c5 C (O) OR ^a5 , S (O) R ^{b5 , S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 1,2,3,4 selected from R ^d5 are independently Properly it is optionally substituted with five substituents;
Or R ^c and R ^d together with the N atom to which they are attached, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1-6 ^{cyanoalkyl, Cy 2, CN, NO 2}} , OR a5, SR a5, C (O) R b5, C (O) NR c5 R d5, C (O) OR a5, OC (O) R b5, ^{OC (O) NR c5 R d5} , NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, 1, 2 or 3 substituents independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Forming a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted with
R ^c1 and R ^d1 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein the C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 , S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5, 1, 2, 3, 4 Or optionally substituted with 5 substituents;
Or R ^c1 and R ^d1 together with the N atom to which they are attached, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1 _{1-6 ^{cyanoalkyl, Cy 2, CN, NO 2}} , OR a5, SR a5, C (O) R b5, C (O) NR c5 R d5, C (O) OR a5, OC (O) R b5, ^{OC (O) NR c5 R d5} , NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, 1, 2 or 3 substituents independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Forming a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted with
R ^c2 and R ^d2 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocyclo Optionally substituted with alkyl;
Or R ^c2 and R ^d2 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c3 and R ^d3 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocyclo Optionally substituted with alkyl;
Or R ^c3 and R ^d3 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c4 and R ^d4 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocyclo Optionally substituted with alkyl;
Or R ^c4 and R ^d4 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c5 and R ^d5 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocyclo Optionally substituted with alkyl;
Or R ^c5 and R ^d5 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c6 and R ^d6 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein the C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocyclo Optionally substituted with alkyl;
Or R ^c6 and R ^d6 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
L ^B is, OH, halo, -O- (C _1-4 alkyl), - O-with (C _1-4 haloalkyl), and 1, 2, 3, 4 or 5 substituents independently selected from amino Optionally substituted, C _1-4 alkylene;
t1 is 0 or 1; and m, p, q and r are independently selected from 0 and 1.

In some embodiments,
Is CR ^4a R ^5a -CR ^4b R ^5b , -LR ¹ is other than C _1-3 alkyl.

In some embodiments,
Is other than ^{CR 4a R 5a -CR 4b R 5b} .

In some embodiments, R ² is halo, cyano, C ₁ haloalkyl or acetylenyl.

In some embodiments, R ^3a and R ^3b are H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1 -6} cyanoalkyl, Cy ¹ , CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC ^{(O) NR c R d,} NR c R d, NR c C (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d , wherein the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are Cy ¹ , CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^{c R d, NR c R d,} NR c C (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR c Optionally substituted with 1, 2 or 3 substituents independently selected from R ^d , S (O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d .

In some embodiments, Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4. , C (O) R ^b4 , C (O) NR ^c4 R ^d4 , C (O) OR ^a4 , OC (O) R ^b4 , OC (O) NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 C (O ) Independently selected from R ^b4 , NR ^c4 C (O) OR ^a4 , S (O) R ^b4 , S (O) NR ^c4 R ^d4 , S (O) ₂ R ^b4 and S (O) ₂ NR ^c4 R ^d4 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, optionally substituted by 1, 2, 3, 4 or 5 substituents as defined above.

  In some embodiments, X is N.

In some embodiments, X is CR ^3a .

  In some embodiments, X is CH.

  In some embodiments, X is C-Me.

In some embodiments, X is CR ^4a R ^5a .

  In some embodiments, Y is N.

In some embodiments, Y is CR ^3b .

  In some embodiments, Y is CH. In some embodiments, Y is C-Me.

In some embodiments, Y is CR ^4b R ^5b .

In some embodiments, X is NR ^6a and Y is CR ^4b R ^5b .

In some embodiments, X is CR ^4a R ^5a and Y is NR ^6b .

In some embodiments, X is NR ^6a and Y is NR ^6b .

  In some embodiments, X is N and Y is N.

In some embodiments, X is CR ^3a and Y is N.

In some embodiments, X is N and Y is CR ^3b .

In some embodiments, R ^3a and R ^3b are H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ R ^b and NR ^c R ^d , wherein the C _1-6 alkyl, C _2-6 alkenyl and C _{2- 6} Alkynyl is Cy ¹ , CN, NO ₂ , halo, OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC ^{(O) NR c R d,} NR c R d, NR c C (O) R b, NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR ^c R ^d, in ^{_{S (O) 2 R b,}} NR c S (O) 2 R b , and ^{_{S (O) 2 NR c R}} 1,2 or 3 substituents independently selected from ^d Optionally substituted.

In some embodiments, R ^3a and R ^3b are H, C _1-6 alkyl, C _1-6 haloalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ R ^b. And NR ^c R ^d , wherein the C _1-6 alkyl is Cy ¹ , C (O) NR ^c R ^d , C (O) OR ^a , halo, OR ^a , NR ^c R ^d , NR optionally substituted with ^{c C (O) NR c R} d and NR ^{c C} (O) 1,2 or 3 substituents selected from R ^b independently.

In some embodiments, R ^3a and R ^3b are independently selected from H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _1-6 haloalkyl.

In some embodiments, R ^3a and R ^3b are independently selected from H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _1-6 haloalkyl.

In some embodiments, R ^3a and R ^3b are independently selected from H, halo, and C _1-4 alkyl. In some further embodiments, R ^3a and R ^3b are independently selected from H and C _1-4 alkyl. In a further embodiment, R ^3a and R ^3b are independently C _1-4 alkyl.

In some embodiments,
At least one of R ^3a and R ^3b is selected from Cy ¹ ;
Cy ¹ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , OR ^a4 , SR ^a4 , C (O) Aryl, heteroaryl, cyclo, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Cy ³ is selected from alkyl and heterocycloalkyl; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , Selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from NR ^c6 R ^d6 , OR ^a6 and SR ^a6 The

In some embodiments,
R ^3a or R ^3b is Cy ¹ ;
Cy ¹ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , OR ^a4 , SR ^a4 , C (O) Aryl, heteroaryl, cyclo, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Cy ³ is selected from alkyl and heterocycloalkyl; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , Selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from NR ^c6 R ^d6 , OR ^a6 and SR ^a6 The

In some embodiments,
One of R ^3a and R ^3b is selected from Cy ¹ ;
Cy ¹ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , OR ^a4 , SR ^a4 , C (O) Aryl, heteroaryl, cyclo, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Cy ³ is selected from alkyl and heterocycloalkyl; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , Selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from NR ^c6 R ^d6 , OR ^a6 and SR ^a6 The

In some embodiments,
One of R ^3a and R ^3b is Cy ¹ ;
Cy ¹ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , OR ^a4 , SR ^a4 , C (O) Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 And Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 And selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from SR ^a6 .

In some embodiments, one of R ^3a and R ^3b is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, OR ^a4 , SR ^a4 , C ( Aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Selected from.

In some embodiments,
One of R ^3a and R ^3b is Cy ¹ ;
Cy ¹ is each substituted with — (L ^B ) _t1 —Cy ³ and is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, OR ^a4 , SR ^a4 Selected from aryl and heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from: C (O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 And Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 And selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from SR ^a6 .

In some embodiments,
One of R ^3a and R ^3b is Cy ¹ ;
Cy ¹ is each substituted with-(L ^B ) -Cy ³ and is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, OR ^a4 , SR ^a4 , Selected from aryl and heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from C (O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 And Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from SR ^a6 .

In some embodiments,
One of R ^3a and R ^3b is Cy ¹ ;
Cy ¹ is each substituted with -Cy ³ and is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, OR ^a4 , SR ^a4 , C (O) R ^b4 , selected from aryl and heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from C (O) NR ^c4 R ^d4 and C (O) OR ^a4 ; and Cy ³ is Independently of halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 selected substituents.

In some embodiments, at least one of R ^3a and R ^3b is selected from C _1-6 alkyl and C _1-6 haloalkyl, wherein the C _1-6 alkyl is halo, OR ^a , C (O) NR. in ^{c R d, C (O)} oR a, NR c R d, NR c C (O) NR c R d and NR ^{c C} (O) 1,2 or 3 substituents selected from R ^b independently Optionally substituted. In some embodiments, one of R ^3a and R ^3b is selected from C _1-6 alkyl and C _1-6 haloalkyl, wherein the C _1-6 alkyl is halo, OR ^a , C (O) NR ^c. Any of 1, 2 or 3 substituents independently selected from R ^d , C (O) OR ^a , NR ^c R ^d , NR ^c C (O) NR ^c R ^d and NR ^c C (O) R ^b Is replaced by

In some embodiments, at least one of R ^3a and R ^3b is selected from C _1-6 alkyl and C _1-6 haloalkyl, wherein the C _1-6 alkyl is OH, —O— (C _1-4 Alkyl) and optionally substituted with 1, 2 or 3 substituents independently selected from —O—C _1-4 haloalkyl. In some embodiments, one of R ^3a and R ^3b is selected from C _1-6 alkyl and C _1-6 haloalkyl, wherein the C _1-6 alkyl is OH, —O— (C _1-4 alkyl). And optionally substituted with 1, 2 or 3 substituents independently selected from —O—C _1-4 haloalkyl. In a further embodiment, one of R ^3a and R ^3b is C ^1-6 alkyl.

In some embodiments, at least one of R ^3a and R ^3b are -L ^A -Cy ^1, wherein L ^A is halo, one or two substituents independently selected from OR ^a and SR ^a C _1-3 alkylene, optionally substituted with In some embodiments, one of R ^3a and R ^3b is —L ^A —Cy ¹ , wherein L ^A is 1 or 2 substituents independently selected from halo, OR ^a, and SR ^a. C _1-3 alkylene, optionally substituted. In some further embodiments, Cy ¹ is Cy ³ , halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR. with aryl or heteroaryl, each optionally substituted by 1, 2 or 3 substitutions independently selected from ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 is there. In a further embodiment, Cy ¹ is Cy ³ , halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C With 1,2,4-oxadiazolyl, optionally substituted by 1, 2 or 3 substituents independently selected from (O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 is there.

In some embodiments,
At least one of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with Cy ¹ and is independently selected from halo, OR ^a and SR ^a Optionally substituted with a substituent of
Cy ¹ is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

In some embodiments,
One of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with Cy ¹ and is independently selected from halo, OR ^a and SR ^a Optionally substituted with substituents;
Cy ¹ is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

In some embodiments,
At least one of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with Cy ¹ and is independently selected from halo, OR ^a and SR ^a Optionally substituted with a substituent of
Cy ¹ is selected from aryl and heteroaryl, each substituted with R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments,
One of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with Cy ¹ and is independently selected from halo, OR ^a and SR ^a Optionally substituted with substituents;
Cy ¹ is selected from aryl and heteroaryl, each substituted with R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, one of R ^3a and R ^3b is selected from C _1-3 alkyl substituted with 1,2,4-oxadiazolyl, wherein the 1,2,4-oxadiazolyl is Cy ³ and — Substituted with a substituent selected from L ^B -Cy ³ . In some embodiments, one of R ^3a and R ^3b is selected from C _1-3 alkyl substituted with 1,2,4-oxadiazolyl, wherein the 1,2,4-oxadiazolyl is —L ^B —. It is replaced by Cy ^3. In some further embodiments, Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6. Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^d6 , OR ^a6 and SR ^a6 .

In some embodiments, one of R ^3a and R ^3b is selected from C _1-3 alkyl substituted with 1,2,4-oxadiazolyl, wherein the 1,2,4-oxadiazolyl is —Cy ³ Replaced. In some further embodiments, Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6. Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^d6 , OR ^a6 and SR ^a6 .

In some embodiments,
At least one of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with —O—Cy ² and is independently selected from halo, OR ^a and SR ^a Optionally substituted with 1 or 2 substituents;
Cy ² is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

In some embodiments,
One of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with —OCy ² and is independently selected from halo, OR ^a and SR ^a Optionally substituted with a substituent of
Cy ² is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

In some embodiments,
At least one of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with —O—Cy ² and is independently selected from halo, OR ^a and SR ^a Optionally substituted with 1 or 2 substituents;
Cy ² is selected from aryl and heteroaryl, each substituted with Cy ³ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments,
One of R ^3a and R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with —O—Cy ² and is independently selected from halo, OR ^a and SR ^a Or optionally substituted with 2 substituents;
Cy ² is selected from aryl and heteroaryl, each substituted with Cy ³ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, L is — (C _1-18 alkylene)-, optionally substituted with 1, 2, 3, 4 or 5 R ^L1 .
In some embodiments, L is — (C _1-18 alkylene)-.

  In some embodiments, m and q are both 0.

  In some embodiments, m is 0.

  In some embodiments, q is 0.

  In some embodiments, m is 1.

  In some embodiments, q is 1.

  In some embodiments, p is 1.

  In some embodiments, r is 1.

  In some embodiments, p is 0.

  In some embodiments, r is 0.

In some embodiments, R ¹ is H, C _1-10 alkyl, or Cy, wherein the C _1-10 alkyl is optionally substituted with 1, 2, 3, 4, or 5 R ^L2 .

In some embodiments, R ¹ is C _1-10 alkyl optionally substituted with H, 1, 2, 3, 4 or 5 R ^L2 .

In some embodiments, R ¹ is H or C _1-10 alkyl.

In some embodiments, R ¹ is Cy.

In some embodiments, -LR ¹ is C _1-10 alkyl.

In some embodiments, -L-R ¹ is halo, cycloalkyl, optionally substituted with substituents 1, 2, 3, 4 or 5 which are each independently selected from OH and CN, C _{1 -7} alkyl. In some further embodiments, -LR ¹ is C _1-7 alkyl, optionally substituted with ¹ , 2, 3, 4 or 5 halo.

In some embodiments, -L-R ¹ is halo, cycloalkyl, optionally substituted with substituents 1, 2, 3, 4 or 5 which are each independently selected from OH and CN, C _{2 -7} alkyl. In some further embodiments, -LR ¹ is C _2-7 alkyl, optionally substituted with ¹ , 2, 3, 4 or 5 halo.

In some embodiments, -LR ¹ is C _2-7 alkyl. In some embodiments, -LR ¹ is C _3-6 alkyl. In some embodiments, -LR ¹ is C _3-5 alkyl. In some embodiments, -LR ¹ is propyl, butyl, or pentyl.

In some embodiments, -L-R ¹ is halo, cycloalkyl, optionally substituted with substituents 1, 2, 3, 4 or 5 which are each independently selected from OH and CN, C _{4 -6} alkyl.

In some embodiments, -LR ¹ is butyl or pentyl.

In some embodiments, R ² is halo, cyano, C ₁ haloalkyl or acetylenyl.

In some embodiments, R ² is halo, cyano, or C ₁ haloalkyl.

In some embodiments, R ² is halo or C ₁ haloalkyl.

In some embodiments, R ² is Br or CF ₃ .

In some embodiments, R ² is halo. In some further embodiments, R ² is Cl or Br.

In some embodiments, R ² is C ₁ haloalkyl.

In some embodiments, R ² is Br.

In some embodiments, R ² is Cl.

In some embodiments, R ² is CF ₃ .

In some embodiments, R ^4a , R ^4b , R ^5a and R ^5b are H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1- Independently selected from ₆ hydroxyalkyl and C _1-6 cyanoalkyl.

In some embodiments, R ^L1 and R ^L2 are independently selected from halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ and OR ^a2. Is done.

In some embodiments, Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O ) R ^b3 , C (O) NR ^c3 R ^d3 , C (O) OR ^a3 , OC (O) R ^b3 , OC (O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O) R ^b3 , 1, independently selected from NR ^c3 C (O) OR ^a3 , S (O) R ^b3 , S (O) NR ^c3 R ^d3 , S (O) ₂ R ^b3 and S (O) ₂ NR ^c3 R ^d3 , Aryl optionally substituted by 2, 3, 4 or 5 substituents.

  In some embodiments, Cy is aryl.

In some embodiments, Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O ) R ^b3 , C (O) NR ^c3 R ^d3 , C (O) OR ^a3 , OC (O) R ^b3 , OC (O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O) R ^b3 , 1, independently selected from NR ^c3 C (O) OR ^a3 , S (O) R ^b3 , S (O) NR ^c3 R ^d3 , S (O) ₂ R ^b3 and S (O) ₂ NR ^c3 R ^d3 , Heteroaryl optionally substituted by 2, 3, 4 or 5 substituents.

  In some embodiments, Cy is heteroaryl.

In some embodiments, Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O ) R ^b3 , C (O) NR ^c3 R ^d3 , C (O) OR ^a3 , OC (O) R ^b3 , OC (O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O) R ^b3 , 1, independently selected from NR ^c3 C (O) OR ^a3 , S (O) R ^b3 , S (O) NR ^c3 R ^d3 , S (O) ₂ R ^b3 and S (O) ₂ NR ^c3 R ^d3 , Cycloalkyl optionally substituted by 2, 3, 4 or 5 substituents.

  In some embodiments, Cy is cycloalkyl.

In some embodiments, Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O ) R ^b3 , C (O) NR ^c3 R ^d3 , C (O) OR ^a3 , OC (O) R ^b3 , OC (O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O) R ^b3 , 1, independently selected from NR ^c3 C (O) OR ^a3 , S (O) R ^b3 , S (O) NR ^c3 R ^d3 , S (O) ₂ R ^b3 and S (O) ₂ NR ^c3 R ^d3 , Heterocycloalkyl, optionally substituted with 2, 3, 4 or 5 substituents.

  In some embodiments, Cy is heterocycloalkyl.

In some embodiments, Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ₃ , Each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from OR ^a4 , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Independently selected from substituted, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. In some embodiments, Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ₃ , Each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from OR ^a4 , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Independently selected from substituted and aryl and heteroaryl.

In some embodiments, Cy ¹ and Cy ² are independently selected from aryl and heteroaryl, each substituted with R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is selected from Cy ³ and -L ^B -Cy ^3;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, L ^B is halo, OH, -O- (C _1-4 alkyl) and -O- 1, 2 or 3 substituents independently selected from (C _1-4 haloalkyl) C _1-4 alkylene, optionally substituted with In some further embodiments, L ^B is halo, OH, -O- with (C _1-4 alkyl) and -O- 1 or 2 substituents independently selected from (C _1-4 haloalkyl) optionally substituted, a C _1-3 alkylene, in a further embodiment, L ^B is C _1-3 alkylene optionally substituted with OH, in a further embodiment, L ^B is C _1-3 alkylene It is.

In some embodiments, L ^B are optionally substituted with 1, 2 or 3 substituents selected independently from halo and OH, a C _1-4 alkylene. In some embodiments, L ^B is optionally substituted with 1 or 2 substituents independently selected from halo and OH, a C _1-4 alkylene. In some embodiments, L ^B is C _1-4 alkylene optionally substituted with 1 or 2 halo.

In some embodiments, the compounds of the invention have Formula IIa or IIb.
In some embodiments, the compounds of the invention have Formula IIa or IIb, wherein:
L is C _1-18 alkylene;
R ^3a is H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-6 haloalkyl; and R ² is halo or C ₁ haloalkyl.

In some embodiments, the compound of the present invention has Formula IIa1 or IIb1:
Wherein R ^3a , L, R ¹ and R ² are defined as above.

  In some embodiments, the compounds of the invention have Formula IIb1.

In some embodiments, the compounds of the invention have Formula IIb1, wherein -LR ¹ is independently selected from halo, cycloalkyl, OH and CN, respectively Or C _1-7 alkyl, optionally substituted with 5 substituents. In some further embodiments, -LR ¹ is C _2-7 alkyl optionally substituted with ¹ , 2, 3, 4 or 5 halo. In a further embodiment, -LR ¹ is C _2-6 alkyl or C _3-5 alkyl. In a further embodiment, -LR ¹ is propyl, butyl or pentyl. In a further embodiment, -LR ¹ is butyl or pentyl.

In some embodiments, the compounds of the invention have Formula IIb1, wherein R ² is halo or C ₁ haloalkyl. In some further embodiments, R ² is halo. In a further embodiment, R ² is Cl or Br. In some further embodiments, R ² is Cl. In some embodiments, R ² is Br.

  In some embodiments, the compounds of the invention have Formula IIa1.

In some embodiments, the compounds of the invention have Formula IIa1, wherein
-LR ¹ is C _1-7 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, cycloalkyl, OH and CN;
R ² is halo or C ₁ haloalkyl; and R ^3a is H, C _1-6 alkyl, C _1-6 haloalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ Selected from R ^b and NR ^c R ^d , wherein the C _1-6 alkyl is Cy ¹ , C (O) NR ^c R ^d , C (O) OR ^a , halo, OR ^a , NR ^c R ^d , NR optionally substituted with ^{c C (O) NR c R} d and NR ^{c C} (O) 1,2 or 3 substituents selected from R ^b independently.

In some embodiments, the compounds of the invention have Formula IIa, wherein —LR ¹ is independently selected from halo, cycloalkyl, OH and CN, respectively. Or C _2-7 alkyl, optionally substituted with 5 substituents. In some further embodiments, -LR ¹ is C _2-7 alkyl, optionally substituted with ¹ , 2, 3, 4 or 5 halo. In a further embodiment, -LR ¹ is C _2-6 alkyl or C _3-5 alkyl. In a further embodiment, -LR ¹ is propyl, butyl or pentyl.

In some embodiments, the compounds of the invention have Formula IIa, wherein R ^3a is selected from H, C _1-3 alkyl, or C _1-3 haloalkyl. In some further embodiments, R ^3a is selected from H and methyl. In a further embodiment, R ^3a is methyl.

In some embodiments, the compounds of the invention have Formula IIa:
R ^3a is C _1-3 alkyl substituted with Cy ¹ and optionally substituted with 1 or 2 substituents independently selected from halo, OR ^a and SR ^a ;
Cy ¹ is selected from aryl and heteroaryl, each substituted with R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, the compounds of the invention have Formula IIa, wherein R ^3a is selected from C _1-3 alkyl substituted with 1,2,4-oxadiazolyl, wherein the 1,2 , 4-Oxadiazolyl is substituted with a substituent selected from -Cy ³ and -L ^B -Cy ³ . In some further embodiments, Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6. Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^d6 , OR ^a6 and SR ^a6 . In some embodiments, L ^B is, OH, -O- optionally (C _1-4 alkyl) and -O- 1, 2 or 3 substituents independently selected from (C _1-4 haloalkyl) C _1-4 alkylene substituted with

In some embodiments, the compounds of the invention have Formula IIa:
R ^3a is C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with —O—Cy ² and is one or two substituents independently selected from halo, OR ^a and SR ^a Optionally substituted;
Cy ² is selected from aryl and heteroaryl, each substituted with Cy ³ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, the compounds of the invention have Formula IIa, wherein —LR ¹ is C _2-6 alkyl optionally substituted with ¹ , 2, 3, 4 or 5 halo. Yes; R ² is halo; and R ^3a is selected from H, C _1-3 alkyl and C _1-3 haloalkyl. In some further embodiments, R ² is Cl or Br; and R ^3a is methyl.

In some embodiments, the compounds of the invention have Formula III:
In the formula, R ^3b , L, R ¹ and R ² are defined as described above.

In some embodiments, the compounds of the invention have Formula IIIa:
In the formula, R ^3b , L, R ¹ and R ² are defined as described above.

In some embodiments, the compounds of the invention have Formula IIIa, wherein —LR ¹ is independently selected from halo, cycloalkyl, OH, and CN, 1, 2, 3, 4 Or C _1-7 alkyl, optionally substituted with 5 substituents;
R ² is halo or C ₁ haloalkyl; and R ^3b is H, C _1-6 alkyl, C _1-6 haloalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ Selected from R ^b and NR ^c R ^d , wherein the C _1-6 alkyl is Cy ¹ , C (O) NR ^c R ^d , C (O) OR ^a , halo, OR ^a , NR ^c R ^d , NR optionally substituted with ^{c C (O) NR c R} d and NR ^{c C} (O) 1,2 or 3 substituents selected from R ^b independently.

In some embodiments, the compounds of the invention have Formula IIIa, wherein —LR ¹ is independently selected from halo, cycloalkyl, OH, and CN, 1, 2, 3, 4 Or C _2-7 alkyl, optionally substituted with 5 substituents. In some further embodiments, -LR ¹ is C _2-7 alkyl optionally substituted with ¹ , 2, 3, 4 or 5 halo. In a further embodiment, -LR ¹ is C _2-6 alkyl or C _3-5 alkyl. In a further embodiment, -LR ¹ is propyl, butyl or pentyl.

In some embodiments, the compounds of the invention have Formula IIIa, wherein R ^3b is selected from H, C _1-3 alkyl, or C _1-3 haloalkyl. In some further embodiments, R ^3b is selected from H and methyl. In a further embodiment, R ^3b is methyl.

In some embodiments, the compounds of the invention have Formula IIIa:
R ^3b is C _1-3 alkyl substituted with Cy ¹ and optionally substituted with one or two substituents independently selected from halo, OR ^a and SR ^a ;
Cy ¹ is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

In some embodiments, the compounds of the invention have Formula IIIa:
R ^3b is C _1-3 alkyl substituted with Cy ¹ and optionally substituted with one or two substituents independently selected from halo, OR ^a and SR ^a ;
Cy ¹ is selected from aryl and heteroaryl, each substituted with R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, the compounds of the invention have Formula IIIa, wherein R ^3b is selected from C _1-3 alkyl substituted with 1,2,4-oxadiazolyl, wherein the 1,2 , 4-Oxadiazolyl is substituted with a substituent selected from -Cy ³ and -L ^B -Cy ³ . In some further embodiments, Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6. Selected from aryl and heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^d6 , OR ^a6 and SR ^a6 . In some embodiments, L ^B is, OH, -O- optionally (C _1-4 alkyl) and -O- 1, 2 or 3 substituents independently selected from (C _1-4 haloalkyl) C _1-4 alkylene substituted with

In some embodiments, the compounds of the invention have Formula IIIa:
R ^3b is selected from C _1-3 alkyl, wherein the C _1-3 alkyl is substituted with —O—Cy ² and is one or two substituents independently selected from halo, OR ^a and SR ^a Optionally substituted with;
Cy ² is selected from aryl and heteroaryl, each substituted with Cy ³ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 , Aryl and heteroaryl.

In some embodiments, the compounds of the invention have Formula IIIa, wherein R ² is halo. In some further embodiments, R ² is Cl. In other embodiments, R ² is Br.

In some embodiments, the compounds of the invention have Formula IIIa, wherein —LR ¹ is C _2-6 alkyl optionally substituted with ¹ , 2, 3, 4 or 5 halo. Yes; R ² is halo; and R ^3b is selected from H, C _1-3 alkyl and C _1-3 haloalkyl. In some further embodiments, R ² is Cl or Br; and R ^3b is methyl.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is expressly intended that the present invention include each and every individual subcombination of the components of such groups and ranges. For example, the term “C _1-6 alkyl” includes methyl, ethyl, C ₃ alkyl (eg, n-propyl or isopropyl), C ₄ alkyl (eg, n-butyl, isobutyl, t-butyl) or C ₅ alkyl. It is expressly intended to individually disclose (eg n-pentyl, isopentyl or neopentyl) and C ₆ alkyl.

  It is further contemplated that the compounds of the present invention are stable. As used herein, “stable” refers to a compound that is sufficiently robust to survive isolation to a useful purity from the reaction mixture, and preferably capable of formulating an effective therapeutic agent.

  It is further understood that certain features of the invention described in the context of another embodiment for clarity can also be provided in one embodiment in combination. Conversely, the various features of the invention described in the context of one embodiment for the sake of brevity may be provided separately or in any suitable subcombination.

  For compounds of the invention in which a variable appears more than once, each variable may be a different part selected from the Markush group that defines the variable. For example, if a structure is described having two R groups that are present simultaneously in the same compound; the two R groups may represent different moieties selected from the Markush group defined for R.

  As used herein, the term “alkyl” is defined to refer to a saturated hydrocarbon group that is linear or branched. Exemplary alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, t-butyl), pentyl (eg, n-pentyl). , Isopentyl, neopentyl) and the like. The alkyl group can contain 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4 or 1 to about 3 carbon atoms.

As used herein, the term “alkylene” refers to a linking alkyl group. An example of alkylene is —CH ₂ CH ₂ —.

  As used herein, “alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds. Exemplary alkenyl groups include ethenyl, propenyl, and the like.

  As used herein, “alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds. Exemplary alkynyl groups include ethynyl, propynyl and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl include CH ₂ F, CHF ₂ , CF ₃ , C ₂ F ₅ , CCl ₃ , CHCl ₂ , CH ₂ CF ₃ , C ₂ Cl _{5 and the} like.

  As used herein, “aryl” refers to a monocyclic or polycyclic aromatic hydrocarbon (eg, having 2, 3 or 4 fused rings), such as phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aryl group has 6 to about 20 carbon atoms.

  As used herein, “cycloalkyl” refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include monocyclic or polycyclic ring systems (eg, having 2, 3 or 4 fused rings), including spiro rings. In some embodiments, the cycloalkyl group can have 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. it can. Cycloalkyl groups can further have 0, 1, 2 or 3 double bonds and / or 0, 1 or 2 triple bonds. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings that are fused to (ie, have a common bond to) a cycloalkyl ring, eg, benzo derivatives such as pentane, pentene, hexane, and the like. Cycloalkyl groups having one or more fused aromatic rings can be attached via either aromatic or non-aromatic moieties. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, to have an oxo or sulfide substituent. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl and the like.

  As used herein, a “heteroaryl” group refers to an aromatic heterocycle having at least one heteroatom ring component such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic or polycyclic systems (eg, having 2, 3 or 4 fused rings). Any ring-forming N atom in the heteroaryl group can also be oxidized to form the N-oxo moiety. Examples of heteroaryl groups include, without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzoyl Examples include thienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl and the like. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms, and in further embodiments about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

  As used herein, “heterocycloalkyl” refers to a non-aromatic heterocycle in which one or more of the ring-forming atoms is a heteroatom, eg, an O, N, or S atom. Heterocycloalkyl groups include spirocycles in addition to monocyclic or polycyclic ring systems (eg, having 2, 3 or 4 fused rings). Exemplary “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl Pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl and the like. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to a non-aromatic heterocyclic ring (ie, having a common bond thereto), such as phthalimidyl, naphthalimidyl and heterocyclic benzo derivatives. A heterocycloalkyl group having one or more fused aromatic rings can be attached via either an aromatic or non-aromatic moiety. In some embodiments, the heterocycloalkyl group has 1 to about 20 carbon atoms, and in further embodiments, about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and “cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An example of arylalkyl is benzyl, an example of cycloalkylalkyl is —CH ₂ CH ₂ -cyclopropyl.

As used herein, “heteroarylalkyl” refers to an alkyl group substituted by a heteroaryl group, and “heterocycloalkylalkyl” refers to an alkyl substituted by a heterocycloalkyl. An example of heteroarylalkyl is -CH ₂ - (pyridin-4-yl). An example of heterocycloalkylalkyl is —CH ₂ — (piperidin-3-yl).

  As used herein, “halo” or “halogen” includes fluoro, chloro, bromo and iodo.

  As used herein, “hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group.

  As used herein, “cyanoalkyl” refers to an alkyl group substituted with a cyano group.

  The compounds described herein can be asymmetric (eg, having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of how to prepare optically active forms from optically active starting materials are known in the art, for example by resolution of racemic mixtures or by stereoselective synthesis. All such stable isomers, where many geometric isomers of olefins, C═N double bonds, etc. can also be present in the compounds described herein are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention have been described and can be isolated as a mixture of isomers or as separated isomeric forms.

  The compounds of the present invention also include tautomeric forms. Tautomeric forms arise from exchanging single bonds for adjacent double bonds with simultaneous proton transfer. Tautomeric forms include prototropic tautomers, which are isomeric protonated states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs and protons occupy more than one position of the heterocyclic ring system. Cyclic forms that can be made include, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

  The compounds of the present invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

  The term “compound” as used herein is defined to include all stereoisomers, geometric isomers, tautomers and isotopes of the indicated structure.

  All compounds and their pharmaceutically acceptable salts are also defined to include solvated or hydrated forms.

  In some embodiments, the compounds of the invention and their salts are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation includes, for example, compositions rich in the compounds of the invention. For substantial separation, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about Compositions containing 99% by weight of the compounds of the invention or their salts are included. Methods for separating compounds and their salts are routine operations in the art.

  The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as inorganic or organic acid salts of amines; acidic residues such as alkali or organic salts of carboxylic acids. And so on. The pharmaceutically acceptable salts of the present invention include the normal non-toxic salts of the parent compound formed, such as from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Eastern, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is referenced Is incorporated herein in its entirety.

  The phrase “pharmaceutically acceptable” refers here to reasonable benefits / risks within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic responses or other problems or complex conditions. Used to refer to compounds, substances, compositions and / or dosage forms suitable for use in contact with human and animal tissues that are commensurate with the ratio.

  The present invention also includes prodrugs of the compounds described herein. As used herein, “prodrug” refers to any covalently bonded carrier that releases an active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modification is cleaved, either routinely or in vivo, to become the parent compound. For prodrugs, a hydroxyl, amino, sulfhydryl, or carboxyl group is attached to any group that cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively, when administered to a mammalian subject. Compounds are included. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. Prodrugs are prepared and used by T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical. Both are discussed in Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

Synthesis The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the invention can be synthesized using the methods described herein below, together with synthetic methods known in the field of synthetic organic chemistry, or variations thereof, as will be appreciated by those skilled in the art.

  The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions are indicated (eg, reaction temperature, time, reactant mole ratio, solvent, pressure, etc.); it is understood that other process conditions may be used unless otherwise stated Will be done. Optimum reaction conditions may vary according to the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

The methods described herein can be monitored according to any suitable method known in the art. For example, product formation may be performed by spectroscopic means such as nuclear magnetic resonance spectroscopy (eg ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (eg UV-visible) or mass spectroscopy, or chromatography. Can be monitored by chromatography, eg, high performance liquid chromatography (HPLC) or thin layer chromatography.

  The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.

  The reactions of the methods described herein can be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. A suitable solvent is substantially non-reacting with the starting material (reactant), intermediate or product, at the temperature at which the reaction is carried out, ie at a temperature that can range from the freezing temperature of the solvent to the boiling point of the solvent. Can be sex. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, a suitable solvent for the particular reaction step can be selected.

  The compounds of the invention can be prepared, for example, using the reaction pathways and techniques described below.

Scheme 1 describes the synthesis of trifluoromethyl substituted triazolopurinone derivatives 1j and tetrazolopurinone derivatives 1k. Reaction of urea 1a and cyanoacetic acid 1b in the presence of an anhydride, for example Ac ₂ O, gives pyrimidinedione intermediate 1c. After nitrosation of compound 1c with sodium nitrite under appropriate conditions (eg in the presence of acetic acid and aqueous HCl), the resulting nitroso intermediate 1d is reduced with a reducing agent such as Na ₂ S ₂ O _4. By reducing, the diamino intermediate 1e is obtained. Cyclization of diamino intermediate 1e can be achieved by treatment with trifluoroacetic anhydride to give xanthine derivative 1f. After converting 4-carbonyl of xanthine 1f to thiocarbonyl using P ₂ S ₅ , sulfur is selectively methylated using methyl sulfate in an aqueous NaOH solution to produce thioether intermediate 1h. Reaction of the thioether intermediate 1h with hydrazine yields the resulting hydrazone 1i, which is treated with an ortho ester [eg, R ^3a C (O-alkyl) ₃ , eg, R ^3a C (OEt) ₃ ]. To obtain cyclized trizole 1j. Alternatively, intermediate 1i can be treated with NaNO ₂ under suitable conditions (eg, in the presence of an acid such as aqueous HCl) to give cyclized tetrazoloprinone 1j.

Triazolopurinone derivatives of formula 2h can be synthesized according to the procedure illustrated in Scheme 2. Selective alkylation at the 1-position of 7-benzyl-1H-purine-2,6 (3H, 7H) -dione 2a is carried out by alkylating agent R ¹ -L-X ^{1 in} the presence of a base such as sodium carbonate. [Wherein X ¹ can be achieved using a leaving group such as a halide (eg, iodide)]. The resulting alkylated purinedione derivative 2b can be converted to the corresponding thioxoprinone 2c using a reagent such as phosphorus pentasulfide. After methylation with sulfur using methyl sulfate in aqueous NaOH, the resulting thioether 2d is reacted with hydrazine to produce hydrazone intermediate 2e. Cyclization of intermediate 2e with orthoesters [eg R ^3a C (O-alkyl) ₃ , eg R ^3a C (OEt) ₃ ] followed by hydrogenation using eg Pd (OH) ₂ as catalyst Removal of the group yields 2 g of the debenzylated triazole intermediate, which is halogenated (Br or Cl) using a halogenating agent such as N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS). It can be converted to a substituted triazolopurinone derivative 2h.

Halide 2h is further reacted with alkyne 2i (wherein R ^2a can be H, alkyl, alkenyl, CN, NO ₂ , aryl, etc.) under Sonogashira coupling conditions to give aline derivative 2j. (See, eg, Sonogashira, K. et al. Tetrahetron Letter, 1975, 4467; see also Nicolaou, KC Et al. Angew. Chem. Int. Engl. 1991, 30, 1100).

Compounds of formula 3f can be prepared using the procedure shown in Scheme 3. 7-allyl-1H-purine-2,6 (3H, 7H) -dione 3a is converted to an alkylating agent R ¹ -L-X ¹ , for example an alkyl halide (in the formula, The leaving group X ¹ can be region-selectively alkylated at the 3-position using halo). The resulting intermediate 3b is treated with phosphoryl chloride to give intermediate 3c. Treatment of 3c with sodium azide can give tetrazoloprinone intermediate 3d. For example, after removing the allyl group using morpholine in the presence of Pd (PPh ₃ ) ₄ , the compound 3f is obtained by halogenating the intermediate 3e generated using a halogenating reagent such as NBS or NCS. Can do.

Compounds of formula 4g can be prepared using the procedure outlined in Scheme 4. Selective alkylation of the commercially available 4-amino-1H-imidazole-5-carbonitrile (4a) with the amino group by reductive amination with the appropriate aldehyde provides the alkylation product 4b. Reaction of intermediate 4b with hydrazide R ^3b —C (O) —NHNH ₂ gives triazole derivative 4c. Alternatively, carbonitrile 4b can be reacted with sodium hydrogen sulfide to form carbothioamide 4d, which can be methylated to give carbimidothioate 4e. Reaction of carboimide thioate 4e with hydrazide R ^3b —C (O) —NHNH ₂ gives triazole derivative 4c. Cyclization of triazole derivative 4c with 1,1′-carbonyldiimidazole (CDI) gives triazolopurinone 4f. Selective halogenation of 4f using an appropriate halogenating reagent (eg, NBS or NCS) provides 4g of halo-substituted triazolopurinone derivative.

Compounds of formula 5b can be prepared using the procedure described in Scheme 5. Cyclization of the triazole derivative 4c (wherein R ^3c is R ^3a or R ^3b ) using phosgene gives a mixture of triazoloprinones 5a and 4f, which can be obtained by conventional methods, eg, column chromatography Can be separated. Selective halogenation of 5a using a suitable halogenating reagent (eg, NBS or NCS) provides a halo-substituted triazolopurinone derivative of formula 5b.

Compounds of formula 6g can be prepared using the procedure shown in Scheme 6. Coupling (and subsequent cyclization and condensation) of hydroxyimidamide 6a and acid 6b (where n can be 1, 2 or 3) in the presence of CDI provides oxadiazole ester 6c. After saponifying 6c, hydrazide 6e is obtained by coupling with hydrazine under appropriate conditions. Reaction of hydrazide 6e with carboimidothioate 4e at high temperature yields triazolopurinone 6f, which is halogenated with an appropriate halogenating reagent (eg, NBS or NCS) to produce a halo-substituted triazoloprione. Non 6g is obtained.

Compounds of formula 7f can be prepared using the procedure outlined in Scheme 7. Triazole intermediate 7c is obtained by converting commercially available (4-bromophenoxy) acetic acid (7a) to hydrazide 7b using hydrazine and then condensing with carboimide thioate 4e. Cyclization of the triazole derivative 7c in the presence of CDI gives triazolopurinone 7d. Reaction of Formula 7d with Suzuki coupling conditions with known boric acid B (OH) ₂ Cy ^{3 wherein} Cy ³ is an optionally substituted aryl or an optionally substituted heteroaryl group 7e triazolopurinone derivative can be obtained. Selective halogenation of 7e using a suitable halogenating reagent (eg, NBS or NCS) provides a halo-substituted triazolopurinone derivative of formula 7f.

Compounds of formula 5b can also be prepared using the procedure summarized in Scheme 8. Reaction of the commercially available 2,6-dichloropurine (8a) catalyzed by acid with dihydropyran provides the protected 2,6-dichloropurine 8b. Addition of hydrazine to compound 8b yields hydrazinopurine 8c, which is cyclized with an orthoester [eg R ^3a C (O-alkyl) ₃ , eg R ^3a C (OEt) ₃ ] to give triazolopurine. 8d can be obtained. Treatment of chloride 8d with a base, such as LiOH, provides triazolopurin-5-one 8e. Selective alkylation of compound 8e with an alkylating reagent such as alkyl iodide R ¹ -LI in the presence of a base such as K ₂ CO ₃ yields the alkylated triazolopurin-5-one 8f can get. After removal of the tetrahydropyranyl protecting group of compound 8f under acidic conditions [eg in the presence of trifluoroacetic acid (TFA)], the intermediate 8g is selectively halogenated to give a halo-substituted triazolopri of formula 5b. Non-derivatives are obtained.

Pharmaceutical Methods The compounds of the present invention can modulate the activity of the HM74a receptor. The term “modulate” is defined to refer to the ability to increase or decrease the activity of a receptor. Accordingly, the compounds of the invention can be used in a method of modulating the HM74a receptor by contacting the receptor with any one or more of the compounds or compositions described herein. In some embodiments, the compounds of the invention can act as full or partial agonists of the HM74a receptor. In a further embodiment, the compounds of the invention can be used to modulate the activity of the HM74a receptor in an individual by administering a modulating amount of a compound of the invention.

  The present invention further provides a method for treating a disease associated with the HM74a receptor in an individual (eg, a patient), such as dyslipidemia, insulin resistance, hyperglycemia, and the like, which requires such treatment Methods are provided by administering to an individual a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. Exemplary diseases can include any disease, disorder or condition that is directly or indirectly related to the HM74a receptor, eg, a disease, disorder or condition associated with low expression or activity of the HM74a receptor.

  Examples of HM74a receptor related diseases include, but are not limited to, dyslipidemia, highly active antiretroviral therapy (HAART) related lipodystrophy, insulin resistance, diabetes, eg, type 2 diabetes, metabolic Syndrome, atherosclerosis, coronary heart disease, stroke, obesity, high body mass index (BMI), increased abdominal circumference, non-alcoholic fatty liver disease, hepatic steatosis, hypertension and other pathologies such as increased plasma FFA (For example, many of the aforementioned).

  Other diseases that can be treated by administration of the compounds of the invention (and their salts or prodrugs) include chronic inflammatory diseases such as pancreatitis and gout.

  As used herein, the term “dyslipidemia” refers to any one or more of the following diseases or conditions. Low HDL cholesterol, increased cholesterol, increased LDL cholesterol (including any combination of small high density LDL, medium density lipoprotein, very low density lipoprotein and chylomicron), increased total cholesterol / HDL ratio, increased plasma triglycerides Increased circulating free fatty acid levels as well as increased lipoprotein (a).

  In some embodiments, the present invention reduces cholesterol levels in mammals, decreases LDL, decreases total cholesterol / HDL ratio, decreases plasma triglycerides, decreases circulating free fatty acid levels, and reduces lipoproteins A method of reducing (a) or increasing HDL cholesterol is provided by administering to the mammal an effective amount of a compound or composition herein.

  As used herein, the term “cell” is defined to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, the ex vivo cells can be part of a tissue sample excised from an organism, eg, a mammal. In some embodiments, the in vitro cell can be a cell in a cell culture. In some embodiments, the in vivo cell is a cell that lives within an organism, eg, a mammalian body. In some embodiments, the cells are fat cells, pancreatic cells, hepatocytes, neurons or cells that make up the eye.

  As used herein, the term “contact” refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, “contacting” an HM74a receptor with a compound of the present invention includes administering the compound of the present invention to an individual or patient having a HM74a receptor, eg, a human, in addition to, eg, administering the HM74a receptor. Introducing the compound of the present invention into a sample containing cells or purified preparations.

  As used herein, the term “individual” or “patient” used interchangeably refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, It refers to cows, sheep, horses or primates, most preferably humans.

  As used herein, the phrase “therapeutically effective amount” refers to the biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or human. Refers to the amount of active compound or drug that induces

  As used herein, the terms “treat” or “treatment” refer to (1) prevention of a disease; for example, a disease, condition, or disorder that may have a predisposition to that disease, condition, or disorder, but that disease Prevention in individuals who have not yet experienced or exposed to a medical condition or symptomatology; (2) prevention of the disease; for example, experienced or exposed to the disease, condition or disorder, or the condition or general symptoms of the disease, condition or disorder; And (3) recovery of the disease; for example, recovery of the disease, condition or disorder in an individual experiencing or exposing the disease state or gross symptoms of the disease, condition or disorder (ie, disease state and (Or reversal or delay of general symptoms), for example, one or more of reduced severity of the disease.

Combination Therapy The compounds of the present invention can be used in combination with other enzymes or receptor modulators. Examples of other enzyme or receptor modulators include, but are not limited to, any one or more of the following: Steroidal or non-steroidal anti-inflammatory agent (for example, inhibitor of prostaglandin synthesis), inhibitor of PCSK9, inhibitor of ACC1, inhibitor of ACC2, inhibitor of SCD1, inhibitor of DGAT, activator of AMPK , A thyroid receptor modulator, a renin inhibitor, an agent that degrades or inhibits the formation of advanced end products of glycosylation, an HMG-CoA reductase inhibitor (so-called statins), a PPAR alpha agonist or selective modulation Agents, PPAR gamma agonists or selective modulators (both TZD and non-TZD), PPAR delta agonists or selective modulators, PPAR alpha / gamma dual agonists, pan-PPAR (pan-PPAR) agonists or selective modulators, A glucocorticoid receptor antagonist or Selective modulator, bile acid binding resin, NPC1L1 receptor antagonist, cholesterol ester transfer protein inhibitor, apoA-I or synthetic apoA-I / HDL molecule, LXR agonist or selective modulator, FXR agonist or selective modulator, Endothelial lipase inhibitor, liver lipase inhibitor, SR-BI modulator, estrogen receptor agonist or selective modulator, anabolic steroid or steroid derivative, insulin or insulin mimic, sulfonylurea, metformin or other biguanide, DPP-IV Inhibitor, PTP-1B modulator, glucose-6-phosphatase inhibitor, T1-transferase inhibitor, fructose-1,6-bisphosphatase inhibitor, glycogen phosphorylase inhibitor, gluca Gon receptor antagonist, 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor, intestinal lipase inhibitor, neurotransmitter reuptake inhibitor, endocannabinoid receptor antagonist, NPY antagonist, MCH antagonist, MC4R antagonist, GLP-1 or GLP-1 analog (incretin), GLP-1 receptor agonist, thiazide diuretic, beta-adrenergic receptor antagonist, angiotensin II converting enzyme inhibitor, angiotensin II receptor antagonist, calcium channel antagonist and mineralocorticoid A receptor antagonist or a combination thereof.

Pharmaceutical Formulations and Dosage Forms When used as a medicament, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical arts, and vary depending on whether local or systemic treatment is desired and on the area to be treated. Can be administered. Administration is topical (including ocular and mucosal, including intranasal, vaginal and rectal delivery), lung (eg, by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal, Epidermis and transdermal), ocular, oral or parenteral. Methods for ocular delivery include topical administration (instillation), subconjunctival, periocular or intravitreal injection, or introduction with an ocular insert placed surgically in a balloon catheter or conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dosage or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, liquid drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

  The present invention also includes a pharmaceutical composition containing as an active ingredient one or more compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or in the form of a capsule, sachet, paper or other container, for example. Such a carrier is encapsulated. When an excipient serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, these compositions can be used in tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), eg up to 10% by weight Ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing the active compounds of:

  In preparing the formulation, the active compound can be milled to provide the appropriate particle size prior to combination with other active ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active ingredient is substantially water soluble, the particle size can be adjusted by grinding to provide a practically uniform distribution, eg, about 40 mesh, in the formulation.

  The compounds of the present invention can be milled using known milling means such as wet milling to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by methods known in the art, for example see International Patent Application WO 2002/000196.

  Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water , Syrup and methylcellulose. The formulation can further include: Lubricants such as talc, magnesium stearate and mineral oils; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propylhydroxy-benzoates; sweeteners; and flavoring agents. The compositions of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by using procedures known in the art.

  These compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 100 mg, more usually from about 10 to about 30 mg of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit being a predetermined amount calculated to produce the desired therapeutic effect. Of the active substance in association with a suitable pharmaceutical excipient.

  The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, the amount of compound actually administered will usually depend on the condition being treated by the physician, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, patient symptoms It will be understood that it is determined according to the relevant situation including the severity of the disease.

  To prepare a solid composition, such as a tablet, the main active ingredient is mixed with a pharmaceutically acceptable excipient to form a solid pre-blended composition containing a homogeneous mixture of the compounds of the invention. When these pre-blended compositions are referred to as homogeneous, the active ingredient is typically uniformly distributed throughout the composition, and thus the composition is divided into equally effective unit dosage forms such as tablets, pills and capsules. Can be subdivided easily. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

  The tablets or pills of the invention can be coated or otherwise compounded to provide a dosage form that provides the benefits of prolonged action. For example, a tablet or pill can contain an internal dosage and an external dosage component, the latter being in the form of the former upper envelope. These two components can be separated by an enteric layer that resists disintegration in the stomach and allows the internal components to pass intact into the duodenum or to be delayed in release. A variety of materials can be used in such enteric layers or coatings, such materials including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

  Liquid forms in which the compounds and compositions of the invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and edible oils, such as In addition to flavored emulsions with cottonseed oil, sesame oil, coconut oil or peanut oil, elixirs and similar pharmaceutical vehicles are included.

  Compositions for inhalation or insufflation include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions can include the appropriate pharmaceutically acceptable excipients described above. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic effect. The composition can be atomized by using an inert gas. The atomized solution can be breathed directly from the nebulizer, or the nebulizer can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

  The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, eg, prophylaxis or treatment, the condition of the patient, the method of administration and the like. In therapeutic applications, a patient already suffering from a disease can be administered the composition in an amount sufficient to cure or at least prevent symptoms of the disease and its complications. The effective dose depends on the judgment of the attending physician depending on such factors as the severity of the disease, the age, weight and general condition of the patient, as well as the disease state to be treated.

  The composition administered to the patient can be in the form of a pharmaceutical composition as described above. These compositions can be sterilized by conventional sterilization techniques, or can be sterile filtered. Aqueous solutions can be packaged for use as such or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of certain of the aforementioned excipients, carriers or stabilizers results in the formation of pharmaceutical salts.

  The therapeutic dosage of the compounds of the present invention may vary according to, for example, the particular application for which the treatment is being performed, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on several factors including dosage, chemical characteristics (eg, hydrophobicity) and route of administration. For example, the compounds of the present invention can be provided as an aqueous physiological buffer solution for parenteral administration containing from about 0.1 to about 10% w / v compound. Some typical dose ranges are from about 1 μg / kg body weight to about 1 g / kg body weight daily. In some embodiments, the dosage range is from about 0.01 mg / kg body weight to about 100 mg / kg body weight daily. Dosage depends on variables such as the type and extent of disease or disorder progression, the overall health status of the particular patient, the relevant biological efficacy of the selected compound, the formulation of the excipients and the route of administration. Seems to depend. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

  The compounds of the present invention can also be formulated in combination with one or more additional active ingredients that can include any pharmaceutical, eg, antiviral agents, antibodies, immunosuppressive agents, anti-inflammatory agents, and the like.

Labeled Compounds and Assays Another aspect of the invention is not only for imaging, but also for HM74a localization and quantification in tissue samples, including humans, and for identifying HM74a ligands by binding of labeled compounds. It relates to fluorescent dyes, spin lables, heavy metals or radiolabeled compounds of the invention which are useful in both in vitro and in vivo assays. Accordingly, the present invention includes HM74a assays that include such labeled compounds.

The present invention further includes isotopically labeled compounds of the present invention. An “isotopically” or “radiolabeled” compound is defined by an atom having one or more atoms that have an atomic weight or mass number different from the atomic weight or mass number typically found in the natural state (ie, natural). It is a compound of the invention which is exchanged or substituted. Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to, ² H (also described as deuterium D), ³ H (also described as tritium T). ), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I are included. The radionuclide incorporated into the radiolabeled compound of the present invention depends on the specific application of the radiolabeled compound. For example, compounds that incorporate ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I, ³⁵ S are generally most useful for in vitro labeling and competition assays. For radiation imaging applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br are generally most useful.

It is understood that a “radiolabeled” or “labeled compound” is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br.

  Synthetic methods for incorporating radioactive isotopes into organic compounds can be applied to the compounds of the present invention and are well known in the art.

  The radiolabeled compounds of the invention can be used to identify / evaluate compounds in screening assays. In general, newly synthesized or identified compounds (ie, test compounds) can be evaluated for their ability to reduce the binding of radiolabeled compounds of the invention to HM74a. Thus, the ability of a test compound to compete with a radiolabeled compound for binding to HM74a directly correlates with its binding affinity.

Kits The present invention also includes pharmaceutical kits that are useful, for example, in the treatment or prevention of HM74a-related diseases or disorders. These kits can include one or more containers containing a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention. Such kits will be readily apparent to those skilled in the art, if desired, one or more various conventional pharmaceutical kit components, eg, a container comprising one or more pharmaceutically acceptable carriers, Additional containers and the like can be further included. Instructions for use as either an insert or a label may be included in the kit, indicating the amount of the component to be administered, directions for administration and / or directions for mixing the components.

  The present invention will be described in more detail by way of specific examples. The following examples are presented for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to achieve essentially the same results.

  The compounds of the Examples section were found to be agonists or partial agonists of the HM74a receptor according to one or more of the assays presented herein.

General Information All reagents and solvents were obtained from commercial sources and used directly without further purification. LCMS analysis uses a Water SunFire C18 column (2.1 × 50 mm, 5 μM particle size), eluting with 0.025% TFA / water and 0.025% TFA / acetonitrile, mass spectral scan range of 105-900 Da It was performed using. Preparative LCMS purification was performed on a Water FractionLynx system using mass directed fraction and compound-specific method optimization (J. Comb. Chem. 2004, 6, 874-883). I went. The LC method uses 0.1% TFA / water and 0.1% TFA / acetonitrile gradients using a Waters SunFire column (19 × 100 mm, 5 μM particle size) over a total run time of 5 minutes at a flow rate of 30 mL / min. Elute with either (Method A) or elute with a Waters x Bridge C18 column (19 x 100 mm, 5 μM particle size) with 0.15% NH ₄ OH / water and 0.15% NH ₄ OH / acetonitrile gradients (Method B). NMR spectra were obtained using a Varian Mercury-300 or Mercury-400 spectrometer. Chemical shifts are recorded in parts per million (ppm) relative to tetramethylsilane as an internal standard.
Example 1
Preparation of 6-pentyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one
Step A: N-pentylurea

1-isocyanatopentane (5.0 g, 0.044 mol) was added dropwise to a 7.0 M solution of ammonia in methanol (32 mL). After the addition, the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give a white solid that was used directly in the next step without further purification. C ₆ H ₁₅ N ₂ O LCMS calculated for (M + H): 131.1; Found 131.1.
Step B: 6-amino-1-pentylpyrimidine-2,4 (1H, 3H) -dione

A mixture of N-pentylurea (5.8 g, 0.044 mol), acetic anhydride (20 mL, 0.2 mol) and cyanoacetic acid (4.21 g, 0.0495 mol) was stirred at 70 ° C. for 2 hours. After cooling to room temperature, the precipitate was collected by suction filtration, washed with EtOH and air dried to give 6.0 g of solid. The solid was treated with a 3.0 M solution of sodium hydroxide in water (25 mL) at 70 ° C. for 2 hours. After cooling to room temperature, the pH of the reaction mixture was adjusted to neutral with 10N aqueous HCl and the solid formed was collected by filtration to give the desired product as a white solid (4.0 g, yield). 46%). LCMS calculated for _{C 9 H 16 N 3 O 2} (M + H): 198.1; Found 198.0.
Step C: 6-amino-5-nitroso-1-pentylpyrimidine-2,4 (1H, 3H) -dione

Sodium nitrite was added to a stirred mixture of 6-amino-1-pentylpyrimidine-2,4 (1H, 3H) -dione (4.0 g, 0.020 mol) and acetic acid (20 mL, 0.4 mol) in water (20 mL). (1.5 g, 0.022 mol) was added slowly. Stirring was continued at room temperature for 2 hours, at which point the reaction mixture turned pink and a precipitate formed. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in aqueous NaOH and extracted with methylene chloride to remove by-products. The aqueous solution was neutralized with HCl and concentrated. The residue was treated with methanol and filtered. The filtrate was concentrated to give the desired product as a pink solid. LCMS calculated for _{C 9 H 15 N 4 O 3} (M + H): 227.1; Found: 227.1 (M + H), 249.1 (M + Na).
Step D: 5,6-Diamino-1-pentylpyrimidine-2,4 (1H, 3H) -dione

To a mixture of 6-amino-5-nitroso-1-pentylpyrimidine-2,4 (1H, 3H) -dione (1.9 g, 8.3 mmol) and a solution of ammonia in water (20 M, 20 mL) at 70 ° C. Sodium dithionite (3.1 g, 18 mmol) was added slowly. After stirring for 20 minutes, the reaction mixture was concentrated to a volume of about 10 mL and cooled in an ice bath. The greenish solid was collected by filtration and dried under high vacuum for 4 hours to give the desired product (1.5 g, 85% yield). LCMS calculated for _{C 9 H 17 N 4 O 2} (M + H): 213.1; Found: 213.2.
Step E: 3-pentyl-8- (trifluoromethyl) -3,7-dihydro-1H-purine-2,6-dione

A mixture of 5,6-diamino-1-pentylpyrimidine-2,4 (1H, 3H) -dione (1.5 g, 7.1 mmol) and trifluoroacetic anhydride (20 mL, 100 mmol) in DMF (20 mL) was prepared. Heated at 0 ° C. for 1 hour. After most of the unreacted trifluoroacetic anhydride was removed by evaporation under reduced pressure, the remaining solution was transferred to a sealed tube and heated at 120 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with methylene chloride to form a solid precipitate. The solid was filtered to give the desired product (0.81 g, 39.5% yield). _{C 11 H 14 F 3 N 4} O 2 LCMS calculated for (M + H): 291.107; Found: 291.1.
Step F: 3-Pentyl-6-thioxo-8- (trifluoromethyl) -1,3,6,7-tetrahydro-2H-purin-2-one

3-pentyl-8- (trifluoromethyl) -3,7-dihydro-1H-purine-2,6-dione (0.81 g, 2.8 mmol) and phosphorus pentasulfide in 1,4-dioxane (20 mL) A mixture of (1.2 g, 2.8 mmol) was heated at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was by silica gel chromatography (0 to 50% MeOH in CH ₂ Cl ₂₎ was purified twice to give the pure product 0.15g as a yellow solid (0.15g, 18% yield). _{C 11 H 14 F 3 N 4} OS LCMS calculated for (M + H): 307.1; Found: 307.1.
Step G: 6- (Methylthio) -3-pentyl-8- (trifluoromethyl) -3,7-dihydro-2H-purin-2-one

3-pentyl-6-thioxo-8- (trifluoromethyl) -1,3,6,7-tetrahydro-2H-purin-2-one (0.15 g, 0) in aqueous sodium hydroxide (2 M, 2 mL) .49 mmol) was added dimethyl sulfate (0.056 mL, 0.59 mmol). The reaction mixture was heated at 80 ° C. for 1.5 hours, quenched with acetic acid and extracted with methylene chloride. The organic layer was dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the product as a yellow solid (0.15 g, 95% yield). _{C 12 H 16 F 3 N 4} OS LCMS calculated for (M + H): 321.1; Found: 321.1.
Step H: (6E) -3-pentyl-8- (trifluoromethyl) -3,7-dihydro-1H-purine-2,6-dione-6-hydrazone

6- (Methylthio) -3-pentyl-8- (trifluoromethyl) -3,7-dihydro-2H-purin-2-one (0.15 g, 0.23 mmol) and hydrazine in water (0.80 mL) A mixture of (0.80 mL, 25 mmol) was heated at 100 ° C. for 1 hour. The solution was concentrated under reduced pressure and treated azeotropically with toluene twice. The resulting residue was used in the next step without further purification. _{C 11 H 16 F 3 N 6} O LCMS calculated for (M + H): 305.1; Found: 305.1.
Step I: 6-Pentyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

(6E) -3-pentyl-8- (trifluoromethyl) -3,7-dihydro-1H-purine-2,6-dione-6-hydrazone (0.15 g, 0.20 mmol) was added to ethyl orthoformate ( 2 mL, 10 mmol). The mixture was heated at 100 ° C. for 30 minutes, concentrated under reduced pressure, and purified by preparative HPLC to give the desired product. _{C 12 H 14 F 3 N 6} O LCMS calculated for (M + H): 315.1; Found: 315.1.
Example 2
Preparation of 6-butyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 1. _{C 11 H 12 F 3 N 6} O LCMS calculated for: (M + H) 301.1; Found 301.1.
Example 3
Preparation of 6-butyl-3-methyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 1. _{C 12 H 13 F 3 N 6} O LCMS calculated for (M + H): 315.1; Found 315.1.
Example 4
Preparation of 8-bromo-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one
Step A: 2-Amino-7-benzyl-1,7-dihydro-6H-purin-6-one

2-amino-9-[(1S, 2R, 3S, 4S) -2,3-dihydroxy-4- (hydroxymethyl) -cyclopentyl] -1,9-dihydro-6H-purine-6 in DMSO (300 mL) A mixture of -one (60.0 g, 0.213 mol) and benzyl bromide (60.9 mL, 0.512 mol) was stirred at room temperature for 18 hours. Concentrated aqueous HCl (150 mL) was added to the reaction mixture and stirring was continued for 45 minutes. The reaction mixture was poured into MeOH (1800 ml). The solution was neutralized with 2M NaOH solution. The resulting white precipitate was collected by filtration, washed with water and dried under vacuum to give the product (48 g, 93.3%). C ₁₂ H ₁₂ N ₅ O LCMS calculated for (M + H): 242.1; Found: 242.1.
Step B: 7-Benzyl-3,7-dihydro-1H-purine-2,6-dione

Of 2-amino-7-benzyl-3,7-dihydro-6H-purin-6-one (25.0 g, 0.104 mol) in acetic acid (750.0 mL) and water (50.0 mL) at 55 ° C. To the mixture was added dropwise a solution of sodium nitrite (28 g, 0.41 mol) in water (50 mL). After the addition, the mixture was kept stirring for about 30 minutes until there was no remaining starting material, then cooled to room temperature. The reaction mixture was concentrated to about 1/3 of its original volume and diluted with 250 ml of water. The formed precipitate was collected by filtration to give the desired product (20 g, 79.7%). _{C 12 H 11 N 4 O 2} LCMS calculated for (M + H): 243.1; Found: 243.1.
Step C: 7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

7-Benzyl-3,7-dihydro-1H-purine-2,6-dione (5.0 g, 21 mmol) was added in sodium carbonate (3.3 g, 31 mmol) and 1-iodopentane (4. 0 mL, 31 mmol). After stirring at 40 ° C. for 18 hours, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried, filtered and concentrated. The resulting white solid was collected and dried in vacuo at 50 ° C. for 18 hours to give the desired product (2.84 g, 44% yield). LCMS calculated for _{C 17 H 21 N 4 O 2} (M + H): 313.2; Found: 313.2.
Step D: 7-Benzyl-3-pentyl-6-thioxo-1,3,6,7-tetrahydro-2H-purin-2-one

7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 6.4 mmol) and phosphorus pentasulfide (3.0 g, 6.7 mmol) were converted to 1,4- Mixed in dioxane (20 mL). After stirring at 100 ° C. for 6 hours, the reaction mixture was treated with a 2M solution of sodium hydroxide in water (20 mL). The reaction mixture was then adjusted to be acidic (pH about 4) with 2N HCl and extracted with EtOAc. The organic layer was concentrated and the solid formed was washed with ether to give the product as a yellow solid (1.30 g, 61.8% yield). C ₁₇ H ₂₁ N ₄ OS LCMS calculated for (M + H): 329.1; Found: 329.1.
Step E: 7-Benzyl-6- (methylthio) -3-pentyl-3,7-dihydro-2H-purin-2-one

Of 7-benzyl-3-pentyl-6-thioxo-1,3,6,7-tetrahydro-2H-purin-2-one (5.3 g, 16 mmol) in aqueous sodium hydroxide (2M, 50.0 mL). To the mixture was added dimethyl sulfate (2.3 mL, 24 mmol). The reaction mixture was stirred at 80 ° C. overnight, quenched with acetic acid and extracted with dichloromethane (DCM). The organic layer was dried and concentrated to give the desired product (5.2 g, 98% yield). C ₁₈ H ₂₃ N ₄ OS LCMS calculated for (M + H): 343.2; Found: 343.1.
Step F: (6Z) -7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 6-hydrazone

7-benzyl-6- (methylthio) -3-pentyl-3,7-dihydro-2H-purin-2-one (1.2 g, 3.5 mmol) and hydrazine (10 mL, 100 mmol) were mixed. After stirring at 100 ° C. overnight, the solution was concentrated in vacuo. The residue was dissolved in DMSO and purified using preparative LCMS. The product fractions were collected and lyophilized to give the product as a white powder (0.56 g, 60% yield). C ₁₇ H ₂₃ N ₆ O LCMS calculated for (M + H): 327.2; Found: 327.1.
Step G: 9-Benzyl-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

(6Z) -7-Benzyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 6-hydrazone (0.50 g, 1.5 mmol) with ethyl orthoformate (5 mL, 30 mmol). Mixed. After stirring at 60 ° C. for 1 hour, the reaction mixture was concentrated in vacuo. The residue was treated with ether to give the desired product as a white solid (0.25 g, 48.5%). C ₁₈ H ₂₁ N ₆ O LCMS calculated for (M + H): 337.2; Found: 337.1.
Step H: 6-Pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

9-Benzyl-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (0.25 g, 0.74 mmol) in acetic acid (20 mL) ) Was added palladium hydroxide (0.20 g, 1.4 mmol) under N ₂ . Under the mixture H _2, and shaken overnight at 60 psi. Since the reaction was not complete, additional palladium hydroxide (0.2 g, 1.4 mmol) and concentrated HCl (1 mL) were added. Under the resulting mixture H _2, and stirred overnight at 60 psi. The reaction solution was filtered and the filtrate was concentrated in vacuo to give the product as a white solid (0.12 g, 65.6%). C ₁₁ H ₁₅ N ₆ O LCMS calculated for (M + H): 247.1; Found: 247.1.
Step I: 8-Bromo-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (0.12 g in THF (5 mL) in a microwave reaction tube. To a mixture of 0.487 mmol) was added N-bromosuccinimide (0.20 g, 1.1 mmol). The mixture was heated at 70 ° C. in a microwave oven for 12 minutes. After cooling to room temperature, purification using preparative LCMS gave the product (0.011 g). C ₁₁ H ₁₄ BrN ₆ O LCMS calculated for (M + H): 325.0,327.0; Found: 325.0,327.0.
Example 5
Preparation of 8-bromo-6-butyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 4. C ₁₀ H ₁₂ BrN ₆ O LCMS calculated for (M + H): 311.0,313.0; Found: 311.0,313.0.
Example 6
Preparation of 8-bromo-6-butyl-3-methyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 4. C ₁₁ H ₁₄ BrN ₆ O LCMS calculated for (M + H): 325.0,327.0; Found: 325.0,327.0.
Example 7
Preparation of 8-bromo-6-pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one
Step A: 7-allyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione

7-allyl-3,7-dihydro-1H-purine-2,6-dione (10.0 g, 0.052 mol), sodium carbonate (8.3 g, 0.078 mol) and 1-iodo in DMF (100 mL) A mixture of pentane (12 g, 0.062 mol) was stirred at 45 ° C. for 2 days. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was treated with ether and the solid formed was filtered to give the desired product as a white solid (6.2 g, 45.4%). _{C 13 H 19 N 4 O 2} LCMS calculated for (M + H): 263.2; Found: 263.2.
Step B: 7-allyl-6-chloro-3-pentyl-3,7-dihydro-2H-purin-2-one

A mixture of 7-allyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (0.80 g, 3.0 mmol) and phosphoryl chloride (10.0 mL, 100 mmol) was refluxed for 2 hours. Excess phosphoryl chloride was removed by vacuum distillation. The residue was diluted with ice water, neutralized with solid K ₂ CO ₃ and extracted three times with DCM. The combined organic layers were dried, filtered and concentrated to give the crude product (0.60 g), which was used in the next step without further purification. C ₁₃ H ₁₈ ClN ₄ O LCMS calculated for (M + H): 281.1; Found: 281.1.
Step C: 9-allyl-6-pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one

7-Allyl-6-chloro-3-pentyl-3,7-dihydro-2H-purin-2-one (0.65 g, 2.3 mmol ) and sodium azide (0.98 g, 15 mmol ) in ethanol (20 mL). ) At reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and EtOAc. The organic phase was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by preparative LCMS to give the desired product as a white powder (0.15 g, 22.6%). C ₁₃ H ₁₈ N ₇ O LCMS calculated for (M + H): 288.2; Found: 288.1.
Step D: 6-Pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one

9-Allyl-6-pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one (0.10 g, 0.35 mmol) and morpholine (0.2 mL) in THF (3 mL). , 2.0 mmol) was degassed with N ₂ for 5 min and tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.086 mmol) was added to the mixture. After stirring overnight at room temperature. The reaction mixture was mixed with 2M aqueous HCl and DCM. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The residue was purified using preparative LCMS to give the product as a white powder (0.030 g, 35%). C ₁₀ H ₁₄ N ₇ O LCMS calculated for (M + H): 248.0; Found: 248.0.
Step E: 8-Bromo-6-pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one

6-pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one (0.020 g, 0.081 mmol) and N- in acetonitrile (2 mL) in a 5 mL microwave reaction tube. A mixture of bromosuccinimide (10 mg, 8.0 mmol) was heated at 70 ° C. in a microwave oven for 12 minutes. After cooling to room temperature, the reaction mixture was purified using preparative LCMS to give the desired product as a white powder. C ₁₀ H ₁₃ BrN ₇ O LCMS calculated for (M + H): 326.0,328.0; Found: 326.0,328.0.
Example 8
Preparation of 2-bromo-4-pentyl-8-phenyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one
Step A: 4- (pentylamino) -1H-imidazole-5-carbonitrile

4-Amino-1H-imidazole-5-carbonitrile (10.0 g, 0.0925 mol) and pentanal (11 mL, 0.10 mol) were mixed in methanol (100 mL). After stirring at room temperature for 2 hours, sodium cyanoborohydride (7.0 g, 0.11 mol) was added to the mixture. The mixture was kept stirring overnight. The reaction mixture was concentrated, diluted with EtOAc (1 L) and washed with saturated NaHCO ₃ (30 ml) and then brine (50 ml), respectively. The organic layer was concentrated by dried over Na ₂ SO _4, Combi - was purified by flash silica gel chromatography (20% ~80% EtOAc in hexanes) to give the desired product (11.5 g, 70%) . LCMS calculated for _{C 9 H 15 N 4 (M} + H): 179; Found: 179.1.
Step B: N-pentyl-5- (3-phenyl-1H-1,2,4-triazol-5-yl) -1H-imidazol-4-amine

4- (pentylamino) -1H-imidazole-5-carbonitrile (200 mg, 1.12 mmol), benzohydrazide (229 mg, 1.68 mmol) and potassium carbonate (100 mg, 0) in 1-butanol (6 ml) in a sealed tube. .72 mmol) was stirred at 170 ° C. for 14 hours. The reaction was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative LCMS (Method A) to give the desired product (50 mg, 17% yield). LCMS calculated for C ₁₆ H ₂₁ N ₆ (M + H): 297.2; found 297.1.
Step C: 4-Pentyl-8-phenyl-1,4-dihydro-5H- [1,2,4] triazol [5,1-i] purin-5-one

N-pentyl-5- (3-phenyl-1H-1,2,4-triazol-5-yl) -1H-imidazol-4-amine (50 mg, 0.17 mmol) and N, N-carbonyldiimidazole (50 mg , 0.3 mmol ) was dissolved in THF (10 mL) and stirred at 70 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative LCMS (Method B) to give the desired product (25 mg, 45% yield). C ₁₇ H ₁₉ N ₆ O LCMS calculated for (M + H): 323.2; Found 323.1.
Step D: 2-Bromo-4-pentyl-8-phenyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

Of 4-pentyl-8-phenyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (25 mg, 0.078 mmol) in THF (5 mL). To the mixture was added N-bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to stop the reaction. The reaction mixture was concentrated and the residue was purified by preparative LCMS (Method B) to give the desired product as a white powder. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.25 (m, 2H), 7.50 (m, 3H), 4.31 (t, J = 7.3 Hz, 2H), 1.88 (m, 2H), 1.43 (m, 4H), 0.95 (m, 3H). C ₁₇ H ₁₈ BrN ₆ O LCMS calculated for (M + H): 401.1; Found: 401.0,403.0.
Example 9
Preparation of 2-bromo-8-methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one
Step A: 5- (3-Methyl-1H-1,2,4-triazol-5-yl) -N-pentyl-1H-imidazol-4-amine

To a mixture of 4- (pentylamino) -1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazine (0.33 g, 4.5 mmol) in 1-butanol (10 mL) was added potassium carbonate (0 .10 g, 0.72 mmol) was added. The mixture was sealed and stirred at 165 ° C. for 14 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative LCMS (Method A) to give the desired product (45 mg, 10% yield). LCMS calculated for _{C 11 H 19 N 6 (M} + H): 235.2; Found: 235.1.
Step B: 8-Methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

5- (3-Methyl-1H-1,2,4-triazol-5-yl) -N-pentyl-1H-imidazol-4-amine (45 mg, 0.19 mmol) in THF (10 mL) at 0 ° C. To a solution of was added phosgene in toluene (0.3 mL, 1.0 mmol). The reaction mixture was gradually warmed to room temperature with stirring. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative LCMS (Method A) to give the desired product (25 mg, 50% yield) as a white solid. C ₁₂ H ₁₇ N ₆ O LCMS calculated for (M + H): 261.1; Found: 261.1.
Step C: 2-Bromo-8-methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

Of 8-methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (20 mg, 0.078 mmol) in THF (5 mL). To the mixture was added N-bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to stop the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative LCMS (Method B) to give the desired product as a white powder. C ₁₂ H ₁₆ BrN ₆ O LCMS calculated for (M + H): 339.1; Found: 339.0,341.0.
Example 10
Preparation of 2-bromo-4-pentyl-8-pyridin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 8. C ₁₆ H ₁₇ BrN ₇ O LCMS calculated for (M + H): 402.1; Found: 402.0,404.0.
Example 11
Preparation of 2-bromo-4-pentyl-8-pyridin-3-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 8. ¹ H NMR (400 MHz, CD ₃ OD): δ 9.41 (s, 1H), 8.66 (m, 2H), 7.59 (m, 1H), 4.30 (t, J = 7.9 Hz, 2H), 1.87 (m, 2H), 1.43 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H). C ₁₆ H ₁₇ BrN ₇ O LCMS calculated for (M + H): 402.1; Found: 402.0,404.0.
Example 12
Preparation of 8-bromo-3-methyl-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 4. C ₁₂ H ₁₆ BrN ₆ O LCMS calculated for (M + H): 339.1; Found: 339.0,341.0.
Example 13
Preparation of 8-benzyl-2-bromo-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 8. C ₁₈ H ₁₉ BrN ₆ O LCMS calculated for (M + H): 415.1; Found: 415.1,417.1.
Example 14
Preparation of 2-bromo-4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

Step A: Pyrimidine-4-carbohydrazide

To a solution of pyrimidine-4-carboxylic acid (1.0 g, 8.0 mmol) in THF (15 mL) was added N, N-carbonyldiimidazole (1.4 g, 8.9 mmol). After refluxing for 2 hours, hydrazine (0.8 g, 20 mmol) was slowly added to the reaction mixture at 0 ° C. using a syringe. The reaction mixture was gradually warmed to room temperature and then concentrated to give the desired product as a white solid. C ₅ H ₇ N ₄ O LCMS calculated for (M + H): 139.1; Found: 139.1.
Step B: N-pentyl-5- (3-pyrimidin-4-yl-1H-1,2,4-triazol-5-yl) -1H-imidazol-4-amine

Of methyl 4- (pentylamino) -1H-imidazole-5-carbomidothioate (1.5 g, 6.6 mmol) and pyrimidine-4-carbohydrazide (1.2 g, 8.7 mmol) in ethanol (10 mL). The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure to give the desired product as a light green viscous oil. LCMS calculated for _{C 14 H 19 N 8 (M} + H): 299.2; Found: 299.1.
Step C: 4-Pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (14C1) and 6-pentyl -3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (14C2)

N-pentyl-5- (3-pyrimidin-4-yl-1H-1,2,4-triazol-5-yl) -1H-imidazol-4-amine (2.0 g, 6. mL) in THF (10 mL). 7 mmol ), phosgene 20% in toluene (4.2 g, 8.4 mmol) was added slowly at room temperature using a syringe. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative LCMS (Method A) to give compounds 14C1 and 14C2 (50 mg, 2.3% yield). C ₁₅ H ₁₇ N ₈ O LCMS calculated for (M + H): 325.2; Found: 325.1.
Step D: 2-Bromo-4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (14D1) And 8-bromo-6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (14D2)

4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (14C1) in THF (5 mL) and 6-Pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (14C2) (25 mg, 0.15 mmol) To the mixture was added N-bromosuccinimide (19 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour and then quenched with phenol. After removing the solvent, the residue was purified using preparative LCMS (Method B) to give pure compound (14D1) and pure compound 14D2, respectively. C ₁₅ H ₁₆ BrN ₈ O LCMS calculated for (M + H): 403.1; Found: 403.0,405.0.
Example 15
Preparation of 8-bromo-6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 14. C ₁₅ H ₁₆ BrN ₈ O LCMS calculated for (M + H): 403.1; Found: 403.0,405.0.
Example 16
Preparation of 2-bromo-4-pentyl-8- (trifluoromethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one
Step A: Trifluoroacetic acid hydrazide

To a solution of hydrazine (1.0 g, 31 mmol) in THF (15 mL) at 0 ° C. was slowly added trifluoroacetic anhydride (6.6 g, 31 mmol) using a syringe. After warming to room temperature, the reaction mixture was concentrated to give the desired product as a white solid. _{C 2 H 4 F 3 N 2} O LCMS calculated for (M + H): 129.0; Found: 129.0.
Step B: N-pentyl-5- [3- (trifluoromethyl) -1H-1,2,4-triazol-5-yl] -1H-imidazol-4-amine

A mixture of methyl 4- (pentylamino) -1H-imidazole-5-carbomidothioate (0.53 g, 2.4 mmol) and trifluoroacetic acid hydrazide (0.45 g, 3.5 mmol) in ethanol (10 mL). Refluxed overnight. The reaction mixture was concentrated to give the product as a light green viscous oil. LCMS calculated for _{C 11 H 16 F 3 N 6} (M + H): 289.1; Found: 289.1.
Step C: 4-Pentyl-8- (trifluoromethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (C1) and 6-pentyl -3- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (C2)

N-pentyl-5- [3- (trifluoromethyl) -1H-1,2,4-triazol-5-yl] -1H-imidazol-4-amine (55 mg, 55 ° C.) in THF (10 mL) at 0 ° C. To a mixture of 0.19 mmol) was added 20% phosgene in toluene (0.3 mL, 10 mmol). The reaction mixture was gradually warmed to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative LCMS (Method A) to give the product as a mixture of C1 and C2 (45 mg, 75% yield). C ₁₂ H ₁₄ N ₆ O LCMS calculated for (M + H): 315.1; Found: 315.0.
Step D: 2-Bromo-4-pentyl-8- (trifluoromethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (Dl) And 8-bromo-6-pentyl-3- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (D2)

4-pentyl-8- (trifluoromethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (C1) in THF (5 mL) and 6-Pentyl-3- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one (C2) (45 mg, 0.14 mmol) To the mixture was added N-bromosuccinimide (30 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 1 hour and then quenched with phenol. After removing the solvent, the residue was purified using preparative LCMS (Method B) to give pure compound (D1) and compound D2, respectively. _{D1 C 12 H 13 BrF 3 N} 6 O LCMS calculated for (M + H): 393.0; Found: 393.0,395.0.
Example 17
Preparation of 8-bromo-6-pentyl-3- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 16. ¹ H NMR (400 MHz, d ₆ -DMSO): δ 4.15 (t, J = 7.3 Hz, 2H), 1.73 (m, 2H), 1.31 (m, 4H), 0.85 (t J = 7.0 Hz, 3H). _{C 12 H 13 BrF 3 N 6} O LCMS calculated for (M + H): 393.0; Found: 393.0,395.0.
Example 18
Preparation of 8-chloro-6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one trifluoroacetate

The title compound was prepared using a procedure similar to that described for Example 15. C ₁₅ H ₁₆ ClN ₈ O LCMS calculated for (M + H): 359.1; Found: 359.1.
Example 19
Preparation of 2-chloro-8-methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5, l-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 9. ¹ H NMR (400 MHz, d ₆ -DMSO): δ 4.10 (t, J = 7.5 Hz, 2H), 3.4 (br, 1H), 2.40 (s, 3H), 1.70 (m 2H), 1.29 (m, 4H), 0.84 (t, J = 7.5 Hz, 3H). C ₁₂ H ₁₆ ClN ₆ O LCMS calculated for (M + H): 295.1; Found: 295.1.
Example 20
Preparation of 2-chloro-4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one trifluoroacetate

The title compound was prepared using a procedure similar to that described for Example 14. C ₁₅ H ₁₆ ClN ₈ O LCMS calculated for (M + H): 359.1; Found: 359.1.
Example 21
8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -2-bromo-4-butyl-1,4-dihydro-5H- [1,2,4] triazolo [ Preparation of 5,1-i] purin-5-one
Step A: Methyl 3- (3-benzyl-1,2,4-oxadiazol-5-yl) propanoate

Butanedioic acid, monomethyl ester (4.0 g, 30.3 mmole) and CDI (5.40 g, 33.3 mmole) were dissolved in anhydrous DMF (15 ml) and stirred at room temperature for 3 hours. (1Z) -N′-hydroxy-2-phenylethaneimidamide (5.0 g, 33.3 mmole) was added to the above solution and the mixture was stirred at 90 ° C. for 20 hours. The reaction mixture was concentrated and the residue was diluted with water and EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (eluting with 1: 3 ethyl acetate: hexanes) to give the desired product as a light yellowish oil (5.2 g, 70% yield). LCMS calculated for C ₁₃ H ₁₅ N ₂ O ₃ (M + H): 247.1; found: 247.1,
Step B: 3- (3-Benzyl-1,2,4-oxadiazol-5-yl) propanoic acid

To a solution of methyl 3- (3-benzyl-1,2,4-oxadiazol-5-yl) propanoate (5.2 g, 21.1 mmole) in methanol (30 ml) was added 50 ml of 1N aqueous NaOH. The mixture was stirred at room temperature for 2 hours. After the reaction solution was adjusted to acidic (pH = 3-4) at 0 ° C., the reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product as a colorless oil (4.8 g, 98%). _{C 12 H 13 N 2 O 3} LCMS calculated for (M + H): 233.1; Found: 233.1.
Step C: 3- (3-Benzyl-1,2,4-oxadiazol-5-yl) propanohydrazide

To a solution of 3- (3-benzyl-1,2,4-oxadiazol-5-yl) propanoic acid (1.0 g, 4.3 mmol) in THF (15 mL) was added N, N-carbonyldiimidazole (0.77 g). 4.7 mmol) was added. After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was slowly added to the reaction mixture at 0 ° C. using a syringe. The reaction mixture was gradually warmed to room temperature and then concentrated to give the desired product as a white solid. LCMS calculated for C ₁₂ H ₁₅ N ₄ O ₂ (M + H): 247.1; found: 247.1.
Step D: 5-3- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -1H-1,2,4-triazol-5-yl-N-butyl-1H- Imidazol-4-amine

Methyl 4- (butylamino) -1H-imidazole-5-carbomidothioate (0.80 g, 3.8 mmol) and 3- (3-benzyl-1,2,4-oxadiazole-5 in ethanol (20 mL) A mixture of -yl) propanohydrazide (1.1 g, 4.5 mmol) was refluxed overnight. The reaction mixture was concentrated to give the desired product as a light green viscous oil. C ₂₀ H ₂₅ N ₈ O LCMS calculated for (M + H): 393.2; Found: 393.1.
Step E: 8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -4-butyl-1,4-dihydro-5H- [1,2,4] triazolo [5 , 1-i] purin-5-one

5-3- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -1H-1,2,4-triazol-5-yl in 1,4-dioxane (10 mL) A solution of -N-butyl-1H-imidazol-4-amine (0.90 g, 2.3 mmol) and N, N-carbonyldiimidazole (CDI, 1.0 g, 6.2 mmol) was stirred at 110 ° C. for 2 hours. . The reaction mixture was concentrated and the residue was purified by preparative LCMS (Method A) to give the desired product as a white powder (80 mg, 8.3% yield). LCMS calculated for _{C 21 H 23 N 8 O 2} (M + H): 419.2; Found: 419.1.
Step F: 8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -2-bromo-4-butyl-1,4-dihydro-5H- [1,2,4 ] Triazolo [5,1-i] purin-5-one

8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -4-butyl-1,4-dihydro-5H- [1,2,4] in THF (5 mL) To a mixture of triazolo [5,1-i] purin-5-one (40 mg, 0.096 mmol) was added N-bromosuccinimide (19 mg, 0.11 mmol). After stirring overnight at room temperature, the reaction was quenched with phenol. The reaction mixture was concentrated and the residue was purified by preparative LCMS (Method A) to give the desired product as a white powder. LCMS calculated for _{C 21 H 22 BrN 8 O 2} (M + H): 497.1; Found: 497.0,499.0.
Example 22
8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -4-butyl-2-chloro-1,4-dihydro-5H- [1,2,4] triazolo [ Preparation of 5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 21. LCMS calculated for C ₂₁ H ₂₂ ClN ₈ O ₂ (M + H): 453.2; found: 453.2.
Example 23
2-Bromo-4-butyl-8-[(4-pyridin-4-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purine-5 -Preparation of on-trifluoroacetate
Step A: 2- (4-Bromophenoxy) acetohydrazide

To a solution of (4-bromophenoxy) acetic acid (1.0 g, 4.3 mmol) in THF (15 mL) was added N, N-carbonyldiimidazole (0.84 g, 5.2 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was slowly added to the reaction mixture at 0 ° C. using a syringe. The reaction mixture was gradually warmed to room temperature and then concentrated to give the desired product as a white solid. LCMS calculated for _{C 8 H 10 BrN 2 O 2} (M + H): 245.0; Found: 244.9,246.9.
Step B: 5-3-[(4-Bromophenoxy) methyl] -1H-1,2,4-triazol-5-yl-N-butyl-1H-imidazol-4-amine

Methyl 4- (butylamino) -1H-imidazole-5-carbomidothioate (0.80 g, 3.8 mmol) and 2- (4-bromophenoxy) acetohydrazide (1.0 g, 4 mL) in ethanol (10 mL) .1 mmol) was refluxed overnight. The reaction mixture was concentrated and the residue was purified using combi-flash chromatography (elution: EtOAc / methanol) to give the desired product as a brown oil (1.1 g, 74%). C ₁₆ H ₂₀ BrN ₆ O LCMS calculated for (M + H): 391.1; Found: 391.0,393.0.
Step C: 8-[(4-Bromophenoxy) methyl] -4-butyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

5-3-[(4-Bromophenoxy) methyl] -1H-1,2,4-triazol-5-yl-N-butyl-1H-imidazol-4-amine in 1,4-dioxane (20 mL) ( 1.1 g, 2.8 mmol) and a solution of N, N-carbonyldiimidazole (0.68 g, 4.2 mmol) were stirred at 110 ° C. for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative LCMS (Method A) to give the desired product as a white powder (0.40 g, 38% yield). LCMS calculated for _{C 17 H 18 BrN 6 O 2} (M + H): 417.1; Found: 417.1,419.1.
Step D: 4-Butyl-8-[(4-pyridin-4-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purine-5 on

8-[(4-Bromophenoxy) methyl] -4-butyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (100 mg, 0.24 mmol) ) And 4-pyridinylboronic acid (32 mg, 0.26 mol) were dissolved in N, N-dimethylformamide (3 mL) in a microwave tube. The solution was degassed with N ₂ for 5 minutes before adding dibromo [bis (triphenylphosphoranyl)]-palladium (20 mg, 0.02 mmol) and aqueous sodium carbonate (2M, 1 mL). The reaction mixture was heated at 120 ° C. for 20 minutes using a microwave reactor. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated. The residue was dissolved in DMSO / acetonitrile and purified by preparative LCMS (Method A) to give the desired product as a white powder (30 mg, 24% yield). LCMS calculated for _{C 22 H 22 N 7 O 2} (M + H): 416.2; Found: 417.1.
Step E: 2-Bromo-4-butyl-8-[(4-pyridin-4-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] Purin-5-one trifluoroacetate

4-Butyl-8-[(4-pyridin-4-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purine in THF (5 mL) To a mixture of -5-one (25 mg, 0.060 mmol) was added N-bromosuccinimide (13 mg, 0.072 mmol). The reaction mixture was stirred overnight at room temperature and then quenched with phenol. The reaction mixture was concentrated and the residue was purified by preparative LCMS (Method A) to give the desired product as a white powder. LCMS calculated for _{C 22 H 21 BrN 7 O 2} (M + H): 494.1; Found: 494.0,496.0.
Example 24
4 ′-[(2-Bromo-4-butyl-5-oxo-4,5-dihydro-1H- [1,2,4] triazolo [5,1-i] purin-8-yl) methoxy] biphenyl- Preparation of 3-carbonitrile

The title compound was prepared using a procedure similar to that described for Example 23. _{C 24 H 21 BrN 7 O 2} LCMS calculated for (M + H): 518.1; Found: 518.1,520.1.
Example 25
2-Bromo-4-butyl-8-[(4-pyridin-3-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purine-5 -Preparation of on-trifluoroacetate

The title compound was prepared using a procedure similar to that described for Example 23. LCMS calculated for _{C 22 H 21 BrN 7 O 2} (M + H): 494.1; Found: 494.1,496.1.
Example 26
2-Bromo-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one
Step A: 4- (pentylamino) -1H-imidazole-5-carbothioamide

4- (pentylamino) -1H-imidazole-5-carbonitrile (25 g, 0.14 mol), sodium hydrogen sulfide dihydrate (26 g, 0.28 mol) and ammonium chloride (7.5 g) in methanol (400 mL). , 0.14 mol) was stirred at room temperature overnight. Conversion was about 60% according to analytical LCMS. The mixture was then stirred at 50 ° C. for 3 hours. Methanol was removed and the residue was diluted with water and EtOAc. The organic layer was washed with water and brine respectively, dried and concentrated to give the crude product (30.0 g), which was used in the next step without further purification. C ₉ H ₁₇ N ₄ LCMS calculated for S (M + H): 213.1 ; Found: 213.1.
Step B: Methyl 4- (pentylamino) -1H-imidazole-5-carbomidothioate

To a solution of 4- (pentylamino) -1H-imidazole-5-carbothioamide (1.0 g, 4.7 mmol) in acetone (40 mL) was added methyl iodide (0.80 g, 5.6 mmol) dropwise. . The mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water and ethyl acetate. The organic layer was washed with water and brine, dried and concentrated to give the crude product (1.2 g), which was used in the next step without further purification. C ₁₀ H ₁₉ N ₄ LCMS calculated for S (M + H): 227.1 ; Found: 227.1.
Step C: N-pentyl-5- (1H-1,2,4-triazol-5-yl) -1H-imidazol-4-amine

A mixture of methyl 4- (pentylamino) -1H-imidazole-5-carbomidothioate (0.53 g, 2.4 mmol) and formic hydrazide (0.21 g, 3.5 mmol) in ethanol (10 mL) overnight. Refluxed. The reaction mixture was concentrated under reduced pressure to give the desired product as a slightly green viscous oil. LCMS calculated for _{C 10 H 17 N 6 (M} + H): 221.2; Found: 221.1.
Step D: 4-Pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

N-pentyl-5- (1H-1,2,4-triazol-5-yl) -1H-imidazol-4-amine (0.52 g, 2.4 mmol) and N in 1,4-dioxane (10 mL) , N-carbonyldiimidazole (0.57 g, 3.5 mmol) was stirred at 110 ° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by preparative LCMS to give the desired product (30 mg, 5% yield). C ₁₁ H ₁₅ N ₆ O LCMS calculated for (M + H): 247.1; Found: 247.1.
Step E: 2-Bromo-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

To a mixture of 4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one (20 mg, 0.081 mmol) in THF (5 mL) was added N- Bromosuccinimide (19 mg, 0.11 mol) was added. The reaction mixture was stirred at room temperature for 1 hour and then quenched with phenol. After removing the solvent, the residue was purified by preparative LCMS (Method B) to give the desired product. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.30 (s, 1H), 4.30 (t, J = 7.4 Hz, 2H), 1.86 (m, 2H), 1.41 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H). C ₁₁ H ₁₄ BrN ₆ O LCMS calculated for (M + H): 325.0; Found: 325.0,327.0.
Example 27
Preparation of 2-bromo-4-butyl-8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. ¹ H NMR (400 MHz, d ₆ -DMSO): δ 4.01 (t, J = 7.3 Hz, 2H), 2.72 (s, 3H), 1.66 (m, 2H), 1.32 (m 2H), 0.89 (t, J = 7.4 Hz, 3H). C ₁₁ H ₁₄ BrN ₆ O LCMS calculated for (M + H): 325.0; Found: 325.1,327.1.
Example 28
Preparation of 2-chloro-8-methyl-4-propyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. ¹ H NMR (300 MHz, CD ₃ OD): δ 4.20 (t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 1.85 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). C ₁₀ H ₁₂ ClN ₆ O LCMS calculated for (M + H): 267.1; Found: 267.1.
Example 29
Preparation of 2-bromo-8-methyl-4-propyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. ¹ H NMR (400 MHz, CD ₃ OD): δ 4.23 (t, J = 7.3 Hz, 2H), 2.49 (s, 3H), 1.86 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). C ₁₀ H ₁₂ BrN ₆ O LCMS calculated for (M + H): 311.0; Found: 311.0,313.0.
Example 30
Preparation of 4-butyl-2-chloro-8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. ¹ H NMR (300 MHz, CD ₃ OD): δ 4.28 (t, J = 7.7 Hz, 2H), 2.51 (s, 3H), 1.82 (m, 2H), 1.44 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). C ₁₁ H ₁₄ ClN ₆ O LCMS calculated for (M + H): 281.1; Found: 281.1.
Example 31
Preparation of 8-bromo-6-pentyl-3-methyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 4. C ₁₂ H ₁₆ BrN ₆ O LCMS calculated for (M + H): 339.0,341.0; Found: 339.0,341.0.
Example 32
Preparation of 8-bromo-6-isobutyl-6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one
Step A: 2,6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

2,6-dichloropurine (22.0 g, 116.4 mmol), dihydropyran (11.5 mL, 126 mmol) and D-(+)-10-camphor sulfonic acid (2.D) in 1,2-dichloroethane (300 mL). 20 g, 9.47 mmol) was stirred at 83 ° C. for 16 hours. The first white suspension turned yellow and then black after 2 hours. The reaction mixture was diluted with CCl ₃ H and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated and triturated 3 times with hexanes to give the desired product. ¹ H NMR (300 MHz, CCl ₃ D): δ 8.33 (s, 1H), 5.75 (dd, J = 10.4 Hz, 2.5 Hz, 1H), 4.18 (m, 2H), 3. 79 (m, 2H), 1.84 (m, 4H).
Step B: 2-Chloro-6-hydrazino-9- (tetrahydro-2H-pyran-2-yl) -9H-purine

To a suspension of 2,6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (5 g, 20 mmol) in 1-butanol (75 mL) was added hydrazine hydrate (2.0 ml, 40 mmol) was added at room temperature. The mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the desired product. C ₁₀ H ₁₄ ClN ₆ O LCMS calculated for (M + H): 269.1; Found: 269.0.
Step C: 5-Chloro-7- (tetrahydro-2H-pyran-2-yl) -7H- [1,2,4] triazolo [3,4-i] purine

(6Z) -2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -1,9-dihydro-6H-purin-6-onehydrazone [this is 2-chloro-6-hydrazino-9- ( Tetrahydro-2H-pyran-2-yl) -9H-purine; a mixture of 0.1 g, 0.5 mmol] and ethyl orthoformate (3 g, 20 mmol) was stirred at 98 ° C. for 12 hours. . The reaction mixture was concentrated under reduced pressure to give the product. C ₁₁ H ₁₂ ClN ₆ O LCMS calculated for (M + H): 279.1; Found: 279.0.
Step D: 7- (Tetrahydro-2H-pyran-2-yl) -6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

5-Chloro-7- (tetrahydro-2H-pyran-2-yl) -7H- [1,2,4] triazolo [3,4-i] purine (0.17 g, 0.50 mmol in THF (10 mL) ) Was added lithium hydroxide (420 mg, 18 mmol) and water (10 mL). After stirring for 10 minutes at room temperature. The reaction mixture is concentrated under reduced pressure to give the product, which is used in the next step without further purification. _{C 11 H 13 N 6 O 2} LCMS calculated for (M + H): 261.1; Found: 261.0.
Step E: 6-Isobutyl-7- (tetrahydro-2H-pyran-2-yl) -6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

7- (Tetrahydro-2h-pyran-2-yl) -6,7-dihydro-5h- [1,2,4] triazolo [3,4-i] purin-5-one (2) in DMF (20 ml) To a solution of 0.08 g, 4.0 mmol) was added potassium carbonate (1.10 g, 8.0 mmol) and isobutyl iodide (1.47 g, 8.0 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the product. _{C 15 H 21 N 6 O 2} LCMS calculated for (M + H): 317.2; Found: 317.1.
Step F: 6-isobutyl-6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

6-Isobutyl-7- (tetrahydro-2H-pyran-2-yl) -6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] in methylene chloride (0.8 mL) To a solution of purin-5-one (20 mg, 0.06 mmol) was added TFA (0.1 mL, 1 mmol) dropwise. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated to give the crude product, which was used in the next step without further purification. C ₁₀ H ₁₃ N ₆ O LCMS calculated for (M + H): 233.1; Found: 233.1.
Step G: 8-Bromo-6-isobutyl-6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

To a solution of 6-isobutyl-6,7-dihydro-5h- [1,2,4] triazolo [3,4-i] purin-5-one (9.4 mg, 40 mmol) in THF (5 ml) was added N- Bromosuccinimide (8 mg, 44.7 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was purified by preparative LCMS (Method A) to give the desired product. C ₁₀ H ₁₂ BrN ₆ O LCMS calculated for (M + H): 311.0; Found 310.9,313.0.
Example 33
5- (8-Bromo-5-oxo-5H- [1,2,4] triazolo [3,4-i] purin-6 (7H) -yl) pentanenitrile

The title compound was prepared using a procedure similar to that described for Example 32. C ₁₁ H ₁₁ BrN ₇ O LCMS calculated for (M + H): 336.0; Found 336.0,338.0.
Example 34
8-Bromo-6- (3,3,3-trifluoropropyl) -6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 32. _{C 9 H 7 BrF 3 N 6} O LCMS calculated for (M + H): 351.0; Found: 351.0,353.0.
Example 35
8-Bromo-6- (2-cyclohexylethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 32. LCMS calculated for C ₁₄ H ₁₈ BrN ₆ O (M + H): 365.1; found 365.1, 367.1.
Example 36
8-Bromo-6- (3-methylbutyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 32. ¹ H NMR (300 MHz, d ₆ -DMSO): δ 8.49 (s, 1H), 4.62 (t, J = 6.5 Hz, 2H), 1.81 (m, 1H), 1.74 (m 2H), 0.95 (t, J = 6.5 Hz, 3H). C ₁₁ H ₁₄ BrN ₆ O LCMS calculated for (M + H): 325.0; Found 325.0,327.0.
Example 37
2-Bromo-8-methyl-4- (4,4,4-trifluorobutyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one Preparation of

The title compound was prepared using a procedure similar to that described for Example 26. ¹ H NMR (400 MHz, d ₆ -DMSO): δ 4.21 (t, J = 7.2 Hz, 2H), 2.1 (s, 3H), 2.38 (m, 2H), 1.95 (m 2H). _{C 11 H 11 BrF 3 N 6} O LCMS calculated for (M + H): 379.0,381.0; Found: 379.0,381.0.
Example 38
2-Bromo-8-methyl-4- (5,5,5-trifluoropentyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one Preparation of

The title compound was prepared using a procedure similar to that described for Example 26. _{C 12 H 13 BrF 3 N 6} O LCMS calculated for (M + H): 393.0,395.0; Found: 393.0,395.0.
Example 39
2-Bromo-8-methyl-4- (3,3,3-trifluoropropyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one Preparation of

The title compound was prepared using a procedure similar to that described for Example 26. _{C 10 H 9 BrF 3 N 6} O LCMS calculated for (M + H): 365.0,367.0; Found: 365.0,367.0.
Example 40
Preparation of 2-bromo-4- (4-fluorobutyl) -8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. C ₁₁ H ₁₃ BrFN ₆ O LCMS calculated for (M + H): 343.0,345.0; Found: 343.0,345.0.
Example 41
Preparation of 2-bromo-4- (5-fluoropentyl) -8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. C ₁₂ H ₁₅ BrFN ₆ O LCMS calculated for (M + H): 357.0,359.0; Found: 357.0,359.0.
Example 42
Preparation of 2-bromo-4- (3-fluoropropyl) -8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. C ₁₀ H ₁₁ BrFN ₆ O LCMS calculated for (M + H): 329.0,331.0; Found: 329.0,331.0.
Example 43
Preparation of 2-bromo-4-butyl-8- (4-methoxyphenyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. LCMS calculated for _{C 17 H 18 BrN 6 O 2} (M + H): 417.1,419.1; Found: 417.0,419.0.
Example 44
Preparation of 2-bromo-4-butyl-8- (4-hydroxyphenyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. LCMS calculated for C ₁₆ H ₁₆ BrN ₆ O ₂ (M + H): 403.0, 405.0; found: 403.0, 405.0.
Example 45
Preparation of 2-bromo-4-butyl-8- (4-methoxybenzyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. _{C 18 H 20 BrN 6 O 2} LCMS calculated for (M + H): 431.1,433.1; Found: 431.0,433.0.
Example 46
Preparation of 2-bromo-4-butyl-8- (4-hydroxybenzyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. LCMS calculated for _{C 17 H 18 BrN 6 O 2} (M + H): 417.1,419.1; Found: 417.0,419.0.
Example 47
Preparation of 2-bromo-4-butyl-8- (methoxymethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one

The title compound was prepared using a procedure similar to that described for Example 26. _{C 12 H 16 BrN 6 O 2} LCMS calculated for (M + H): 355.0,357.0; Found: 355.0,357.0.
Example A
GTPγS recruitment assay

Membranes were prepared from HEK293 cells transiently transfected with human HM74a and Gα ₀ proteins. The assay was performed in a 384 well format with a volume of 50 μL per assay point. Serial dilutions of compounds are prepared in assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl ₂ , 10 mg / L saponin and 10 μM GDP), membrane (2 μg per assay point) and ³⁵ S in assay buffer. Mixed with GTPγS (Amersham, 0.3 nM). The mixtures were incubated for 30 minutes at room temperature and wheat germ agglutinin SPA beads (Amersham) (0.2 mg per assay point) in assay buffer were added. After incubation for 30 minutes with agitation, the bound ³⁵ S GTPγS was determined by centrifuging the plate at 1500 g for 5 minutes and counting in a TopCount scintillation counter. Active compounds from this assay have an EC _{50 of} about 50 μM or less. In some embodiments, the compound of the invention is less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 20 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than 300 nM, or less than about 200 nM. EC ₅₀ of For example, the compound of Example 1 has an EC ₅₀ of 61 nM in this assay.
Example B
Nicotinic acid substitution assay

Membranes were prepared from HEK293 cells transiently transfected with human HM74a and Gα ₀ proteins. Wheat germ agglutinin SPA beads (Amersham) were weighed and suspended in assay buffer (50 mM Tris-HCl, pH 7.5, 1 mM MgCl ₂ and 0.02% CHAPS). The beads were mixed with the membrane (75 μg membrane / mg bead) for 1 hour at room temperature. The beads were spun down and washed once with buffer and then resuspended in buffer at 5 mg beads / ml. 20 nM ³ H nicotinic acid was added to the beads and then mixed with the compound (50 μL total volume). Nonspecific binding was determined by including 100 μM nicotinic acid. The binding mixtures were incubated overnight at room temperature with agitation. The bound ³ H nicotinic acid was determined by centrifuging the plate at 1500 g for 5 minutes and counting in a TopCount scintillation counter. Active compounds from this assay have an IC _{50 of} about 50 μM or less. In some embodiments, the compound of the invention is less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 20 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than 300 nM, or less than about 200 nM. Having an IC ₅₀ of
Example C
FLIPR assay

HEK293e cells transfected with human HM74a and Gα ₁₆ DNA were seeded the day before the assay at 50,000 cells / well in a 384-well plate. The cells were washed once with 1 × HBSS and incubated with FLIPR Calcium 3 (Molecular Devices) dye for 60 minutes in HBSS buffer containing 1 × 3 mM probenecid and 5% CO ₂ at 37 ° C. Compounds were added to the cell plate and fluorescence was measured changes due G.alpha ₁₆ mediated intracellular calcium response. Active compounds from this assay have an EC _{50 of} about 50 μM or less. In some embodiments, the compound of the invention is less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 20 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than 300 nM, or less than about 200 nM. EC ₅₀ of
Example D
cAMP assay

CHO cells stably transfected with human HM74a were seeded at 7,500 cells / well in HAMS F12 medium containing 10% FBS in 96-well plates. The plate was incubated overnight at 37 ° C. and 5% CO ₂ . Test compounds were prepared in stimulation buffer containing 1 × HANKS, 20 mM HEPES, 5 μM forskolin and 0.25 mM IBMX. After removing the media from the cell plate, 30 μL of test compound was added. After 30 minutes incubation at 37 ° C. and 5% CO ₂ , cAMP levels were assayed using the HitHunter cAMP XS assay kit (DiscoverX, CA). IC ₅₀ determination was based on compound inhibition relative to DMSO control. Active compounds from this assay have an IC _{50 of} about 100 μM or less. In some embodiments, the compound of the present invention is less than about 100 μM, less than about 80 μM, less than about 60 μM, less than about 40 μM, less than about 30 μM, less than about 20 μM, less than about 10 μM, less than about 5 μM, less than about 1 μM, about 500 nM. Having an IC ₅₀ of less than, less than 300 nM or less than about 200 nM. For example, the compound of Example 1 has an IC ₅₀ of 20 nM in this assay.
Example E
Adipocyte lipolysis assay

Preadipocytes purchased from Zen Bio were cultured in 96-well plates at 8.7 × 10 ⁴ cells / well and differentiated for 14 days, and mature adipocytes were assayed between days 15-21. Adipocyte maturation is determined by the presence of rounded cells with giant lipid droplets in the cytoplasm. After maturation, cells were washed and incubated overnight with various concentrations of compounds diluted in assay buffer containing IBMX (100 μM) and 0.1% final DMSO concentration. After overnight culture, the glycerol concentration in the supernatant was determined with a Lipolysis Assay Kit purchased from Zen-Bio. The absorbance at 540 nm is directly proportional to the glycerol concentration in the sample. IC ₅₀ determination was based on compound inhibition relative to DMSO control. Active compounds from this assay have an IC _{50 of} about 10 μM or less. In some embodiments, the compounds of the invention have an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 2 μM, less than about 1 μM, less than about 500 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than about 50 nM. For example, the compound of Example 1 has an IC ₅₀ of 100 nM in this assay.

  In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications and publications, is hereby incorporated by reference in its entirety.

Claims (39)

A compound of formula I below or a pharmaceutically acceptable salt thereof .


(Where
The dashed line indicates any bond;
X is N ;
Y is N, CR ^3b , CR ^4b R ^5b or NR ^6b ;
L is optionally substituted by 1, 2, 3, 4 or 5 R ^L1 ,-(C _1-6 alkylene)-(Q ¹ ) _m- (C _1-6 alkylene) _p- (Q ² ) _q- (C _1-6 alkylene) _r- where m and q are both 1 and p is 1;
R ¹ is H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or Cy, wherein the C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl is 1, Optionally substituted with 2, 3, 4 or 5 R ^L2 ;
R ² is halo, cyano, C ₁ haloalkyl or acetylenyl, wherein the acetylenyl is C _1-6 alkyl, C _2-6 alkenyl, C _2-10 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl Optionally substituted with a substituent selected from C _1-6 cyanoalkyl, Cy ⁴ , CN, NO ₂ , C (O) R ^b6 , C (O) NR ^c6 R ^d6 or C (O) OR ^a6 ;
R ^3b is H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ¹ , CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^{c R d, NR c C (O} ) R b, NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR c R d, S ( O) ₂ R ^b , NR ^c S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d , independently selected from C _1-6 alkyl, C _2-6 alkenyl and C _2-6 Alkynyl is Cy ¹ , CN, NO ₂ , halo, OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC ( ^{O) NR c R d, NR} c R d, NR c C (O ) R ^b , NR ^c C (O) NR ^c R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) NR ^c R ^d , S (O) ₂ R ^b , NR ^c Optionally substituted with 1, 2 or 3 substituents independently selected from S (O) ₂ R ^b and S (O) ₂ NR ^c R ^d ;
R ^4b and R ^5b are H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 , wherein said C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl _{^{Cy 2, CN, NO 2,}} OR a1, SR a1, C (O) R b1, C (O) NR c1 R d1, C (O) OR a1, OC (O) R b1, OC (O) NR ^c1 R ^{d 1} , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , S (O) R ^b1 , S (O) NR ^c1 R optionally substituted with 1, 2 or 3 substituents independently selected from ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 ;
R ^6b is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, Cy ² , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C ( Independent of O) OR ^a1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) ₂ NR ^c1 R ^d1 Wherein the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are Cy ² , CN, NO ₂ , OR ^a1 , SR ^a1 , C (O) R ^b1 , C (O) NR ^c1 R ^d1 , C (O) OR ^a1 , OC (O) R ^b1 , OC (O) NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C (O) R ^b1 , NR ^c1 C (O) NR ^c1 R ^d1 , NR ^c1 C (O) OR ^a1 , S (O) R ^b1 , S (O) NR ^c1 R ^d1 , S (O) ₂ R ^b1 , NR ^c1 S (O) ₂ R ^b1 and S (O) also 1, 2 is selected from ₂ NR ^c1 R ^d1 are independently Ku is optionally substituted with 3 substituents;
R ^L1 and R ^L2 are halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O) R ^b2 , C (O) NR ^c2 R ^d2 , C (O) OR ^a2 , OC (O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C ( ^{O) NR c2 R d2, NR} c2 C (O) oR a2, S (O) R b2, S (O) NR c2 R d2, S (O) 2 R b2, NR c2 S (O) 2 R b2 and Independently selected from S (O) ₂ NR ^c2 R ^d2 ;
Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O) R ^b3 , C (O ^{) NR c3 R d3, C (} O) OR a3, OC (O) R b3, OC (O) NR c3 R d3, NR c3 R d3, NR c3 C (O) R b3, NR c3 C (O) OR ^{a3, S (O) R b3} , S (O) NR c3 R d3, S (O) 2 R b3 and S (O) ₂ NR ^c3 1,2,3,4 or 5 is selected from R ^d3 are independently Selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by a substituent of
Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , CN, NO ₂ , OR ^a4. , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 , C (O) OR ^a4 , OC (O) R ^b4 , OC (O) NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 From C (O) R ^b4 , NR ^c4 C (O) OR ^a4 , S (O) R ^b4 , S (O) NR ^c4 R ^d4 , S (O) ₂ R ^b4 and S (O) ₂ NR ^c4 R ^d4 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 independently selected substituents;
Cy ³ and Cy ⁴ are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO ₂ , OR ^a6 , SR ^a6 , C (O) R ^b6 , C (O) NR ^c6 R ^d6 , C (O) OR ^a6 , OC (O) R ^b6 , OC (O) NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C (O) R ^b6 , NR ^c6 C (O) OR ^a6 , S (O) R ^b6 , S (O) NR ^c6 R ^d6 , S (O) ₂ R ^b6 and S (O) ₂ NR ^c6 R independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from ^d6 ;
Q ¹ and Q ² are O, S, NH, CH ₂ , CO, CS, SO, SO ₂ , OCH ₂ , SCH ₂ , NHCH ₂ , CH ₂ CH ₂ , COCH ₂ , CONH, COO, SOCH ₂ , SONH, Independently selected from SO ₂ CH ₂ and SO ₂ NH;
R ^a and R ^a1 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 is selected from R ^d5 are independently 1,2,3, Or optionally substituted with five substituents;
R ^a2 , R ^a3 , R ^a4 , R ^a5 and R ^a6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Independently selected from cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl , Heteroarylalkyl, cycloalkyl or Optionally substituted with Russia cycloalkyl;
R ^b and R ^b1 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 is selected from R ^d5 are independently 1,2,3, Or optionally substituted with five substituents;
R ^b2 , R ^b3 , R ^b4 , R ^b5 and R ^b6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, hetero Independently selected from cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , Aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl , Heteroarylalkyl, cycloalkyl or Optionally substituted with Russia cycloalkyl;
R ^c and R ^d are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 is selected from R ^d5 are independently 1,2,3, Or optionally substituted with five substituents;
Or R ^c and R ^d together with the N atom to which they are attached, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1-6 ^{cyanoalkyl, Cy 2, CN, NO 2}} , OR a5, SR a5, C (O) R b5, C (O) NR c5 R d5, C (O) OR a5, OC (O) R b5, ^{OC (O) NR c5 R d5} , NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, 1, 2 or 3 substituents independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Forming a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted with
R ^c1 and R ^d1 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 1, 2, 3, independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Optionally substituted with 4 or 5 substituents;
Or R ^c1 and R ^d1 together with the N atom to which they are attached, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1 _{1-6 ^{cyanoalkyl, Cy 2, CN, NO 2}} , OR a5, SR a5, C (O) R b5, C (O) NR c5 R d5, C (O) OR a5, OC (O) R b5, ^{OC (O) NR c5 R d5} , NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, 1, 2 or 3 substituents independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Forming a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted with
R ^c2 and R ^d2 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c2 and R ^d2 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c3 and R ^d3 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c3 and R ^d3 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c4 and R ^d4 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c4 and R ^d4 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c5 and R ^d5 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c5 and R ^d5 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c6 and R ^d6 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c6 and R ^d6 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
L ^B is, OH, halo, -O- (C _1-4 alkyl), - O-with (C _1-4 haloalkyl), and 1, 2, 3, 4 or 5 substituents independently selected from amino Optionally substituted, C _1-4 alkylene;
t1 is 0 or 1; and m, p, q and r are independently selected from 0 and 1) Y is CR ^3b, a compound or pharmaceutically acceptable salt thereof according to claim 1. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is C-Me. Y is N, compounds or pharmaceutical acceptable salts thereof according to claim 1. R ^3b is H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, Cy ¹ , OR ^a , SR ^a , S (O ) R ^b , S (O) ₂ R ^b and NR ^c R ^d independently selected, wherein said C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are Cy ¹ , CN, NO ₂ , Halo, OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^{c R d, NR c C (O} ) R b, NR c C (O) NR c R d, NR c C (O) OR a, S (O) R b, S (O) NR c R d, S ( O) ₂ R ^b, optionally substituted with _{^{NR c S (O) 2 R}} b , and ^{_{S (O) 2 NR c R}} 1,2 or 3 substituents independently selected from ^d, claim 1 compounds according to any one 4 Or pharmaceutically acceptable salts thereof. R ^3b is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ R ^b and NR ^c R ^d Wherein the C _1-6 alkyl is Cy ¹ , C (O) NR ^c R ^d , C (O) OR ^a , halo, OR ^a , NR ^c R ^d , NR ^c C (O) NR ^c R ^d and NR ^{c C} (O) optionally substituted with 1, 2 or 3 substituents selected from R ^b independently, a pharmaceutically acceptable compound or their according to any one of claims 1-5 Possible salt. R ^3b is H, halo, C _1-6 alkyl, C _2-6 alkenyl, independently selected from C _2-6 alkynyl, and C _1-6 haloalkyl, according to any one of claims 1 to 6 A compound or a pharmaceutically acceptable salt thereof. R ^3b is selected from Cy ¹ ;
Cy ¹ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , OR ^a4 , SR ^a4 , C (O) Aryl, heteroaryl, cyclo, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^a4 Selected from alkyl and heterocycloalkyl;
Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 8. Any one of claims 1 to 7 selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from A compound according to one or a pharmaceutically acceptable salt thereof. R ^3b is selected from C _1-6 alkyl and C _1-6 haloalkyl, wherein said C _1-6 alkyl is halo, OR ^a , C (O) NR ^c R ^d , C (O) OR ^a , NR ^c 9. Any one of claims 1 to 8 optionally substituted with 1, 2 or 3 substituents independently selected from R ^d , NR ^c C (O) NR ^c R ^d and NR ^c C (O) R ^b. Or a pharmaceutically acceptable salt thereof. R ^3b is —L ^A —Cy ¹ , wherein L ^A is C _1-3 alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OR ^a and SR ^a. A compound according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof. R ^3b is selected from C _1-3 alkyl, wherein said C _1-3 alkyl is optionally substituted with 1 or 2 substituents substituted with Cy ¹ and independently selected from halo, OR ^a and SR ^a Replaced;
Cy ¹ is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 A compound according to any one of claims 1 to 10 , or a pharmaceutically acceptable salt thereof, selected from:, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. R ^3b is selected from C _1-3 alkyl, wherein said C _1-3 alkyl is optionally substituted with 1 or 2 substituents substituted with Cy ¹ and independently selected from halo, OR ^a and SR ^a Replaced;
Cy ¹ is selected from aryl and heteroaryl, each substituted with R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 The compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, selected from: 1 or 2 substituents wherein R ^3b is selected from C _1-3 alkyl, wherein said C _1-3 alkyl is substituted with —O—Cy ² and is independently selected from halo, OR ^a and SR ^a Optionally substituted with;
Cy ² is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each substituted with 1 or 2 R ⁷ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁷ is independently selected from Cy ³ and —L ^B —Cy ³ at each occurrence;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 13. A compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, selected from:, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. 1 or 2 substituents wherein R ^3b is selected from C _1-3 alkyl, wherein said C _1-3 alkyl is substituted with —O—Cy ² and is independently selected from halo, OR ^a and SR ^a Optionally substituted with;
Cy ² is selected from aryl and heteroaryl, each substituted with Cy ³ and optionally substituted with 1, 2 or 3 R ⁸ ;
R ⁸ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a4 , SR ^a4 , C (O) at each occurrence. R ^b4 , C (O) NR ^c4 R ^d4 and C (O) OR ^{a4 are} independently selected; and Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl, aryl, heteroaryl, CN, NO ₂ , NR ^c6 R ^d6 , OR ^a6 and SR ^a6 14. The compound according to any one of claims 1 to 13 , or a pharmaceutically acceptable salt thereof, selected from: aryl, heteroaryl. 15. A compound according to any one of claims 1 to 14 , or a pharmaceutically acceptable salt thereof, wherein L _is- ( _C1-18 alkyl)-. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 , wherein R ¹ is H or C _1-10 alkyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 , wherein -LR ¹ is C _1-10 alkyl. -LR ¹ is C _3-7 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, cycloalkyl, OH and CN. Item 18. The compound according to any one of Items 1 to 17 , or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, wherein -LR ¹ is butyl or pentyl. R ² is halo, cyano, C ₁ haloalkyl or acetylenyl compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19. R ² is halo, cyano or C ₁ haloalkyl compound or pharmaceutically acceptable salt thereof according to any one of claims 20 1 to 20. The compound according to any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R ² is halo or C ₁ haloalkyl. R ² is Br or CF _3, the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22. R ² is Br or Cl, the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23. R ² is Br, compound or pharmaceutically acceptable salt thereof according to any one of claims 1-24. R ² is Cl, the compound or a pharmaceutically acceptable salt thereof according to any one of claims to 253. A compound of formula IIa or IIb or a pharmaceutically acceptable salt thereof:


[Where:
L is C _1-18 alkylene;
R ¹ is H, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or Cy, wherein the C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl is 1, Optionally substituted with 2, 3, 4 or 5 R ^L2 ;
R ^3a is H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-6 haloalkyl;
R ² is Ri halo or C ₁ haloalkyl der;
R ^L2 is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O) R ^b2 , C (O ) NR ^c2 R ^d2 , C (O) OR ^a2 , OC (O) R ^b2 , OC (O) NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C (O) R ^b2 , NR ^c2 C (O) NR ^{c2 R d2, NR c2 C (} O) oR a2, S (O) R b2, S (O) NR c2 R d2, S (O) 2 R b2, NR c2 S (O) 2 R b2 , and S (O ₂ ) independently selected from ₂ NR ^c2 R ^d2 ;
Cy is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C (O) R ^b3 , C (O ^{) NR c3 R d3, C (} O) OR a3, OC (O) R b3, OC (O) NR c3 R d3, NR c3 R d3, NR c3 C (O) R b3, NR c3 C (O) OR ^{a3, S (O) R b3} , S (O) NR c3 R d3, S (O) 2 R b3 and S (O) ₂ NR ^c3 1,2,3,4 or 5 is selected from R ^d3 are independently Selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by a substituent of
R ^a2 and R ^a3 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or hetero In cycloalkyl It is replaced by the mind;
R ^b2 and R ^b3 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or hetero In cycloalkyl It is replaced by the mind;
R ^c2 and R ^d2 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c2 and R ^d2 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group; and
R ^c3 and R ^d3 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c3 and R ^d3 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group] A compound of formula IIa1 below or a pharmaceutically acceptable salt thereof.

[Where:
-LR ¹ is C _1-7 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, cycloalkyl, OH and CN;
R ² is halo or C ₁ haloalkyl; and R ^3a is H, C _1-6 alkyl, C _1-6 haloalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ Selected from R ^b and NR ^c R ^d , wherein said C _1-6 alkyl is Cy ¹ , C (O) NR ^c R ^d , C (O) OR ^a , halo, OR ^a , NR ^c R ^d , NR optionally substituted with ^{c C (O) NR c R} d and NR ^{c C} (O) 1,2 or 3 substituents selected from R ^b independently;
Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , CN, NO ₂ , OR ^a4. , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 , C (O) OR ^a4 , OC (O) R ^b4 , OC (O) NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 from ^{C (O) R b4, NR} c4 C (O) oR a4, S (O) R b4, S (O) NR c4 R d4, S (O) 2 R b4 , and _{^{S (O) 2 NR c4 R}} d4 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 independently selected substituents;
Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO ₂ , OR ^a6 , SR ^a6 , C (O) R ^b6 , C (O) NR ^c6 R ^d6 , C (O) OR ^a6 , OC (O) R ^b6 , OC (O) NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C Independent from (O) R ^b6 , NR ^c6 C (O) OR ^a6 , S (O) R ^b6 , S (O) NR ^c6 R ^d6 , S (O) ₂ R ^b6 and S (O) ₂ NR ^c6 R ^d6 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from
R ^a is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1- 6} cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^b5 , OC ( ^{O) NR c5 R d5, NR} c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, S ( ^{O) NR c5 R d5, S} (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) 1, 2, 3, 4 or is selected from ₂ NR ^c5 R ^d5 are independently Optionally substituted with a substituent;
R ^a4 , R ^a5 and R ^a6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Independently selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cyclo Alkyl or heterocycloal Optionally substituted with a kill;
R ^b is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1- 6} cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^b5 , OC ( ^{O) NR c5 R d5, NR} c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, S ( ^{O) NR c5 R d5, S} (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) 1, 2, 3, 4 or is selected from ₂ NR ^c5 R ^d5 are independently Optionally substituted with a substituent;
R ^b4 , R ^b5 and R ^b6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Independently selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cyclo Alkyl or heterocycloal Optionally substituted with a kill;
R ^c and R ^d are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 is selected from R ^d5 are independently 1,2,3, Or optionally substituted with five substituents;
Or R ^c and R ^d together with the N atom to which they are attached, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1-6 ^{cyanoalkyl, Cy 2, CN, NO 2}} , OR a5, SR a5, C (O) R b5, C (O) NR c5 R d5, C (O) OR a5, OC (O) R b5, ^{OC (O) NR c5 R d5} , NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, 1, 2 or 3 substituents independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Forming a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted with
R ^c4 and R ^d4 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c4 and R ^d4 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c5 and R ^d5 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c5 and R ^d5 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c6 and R ^d6 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c6 and R ^d6 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
L ^B is, OH, halo, -O- (C _1-4 alkyl), - O-with (C _1-4 haloalkyl), and 1, 2, 3, 4 or 5 substituents independently selected from amino Optionally substituted, C _1-4 alkylene; and
t1 is 0 or 1] A compound of formula IIa1 below or a pharmaceutically acceptable salt thereof.

(Wherein, be a C _2-6 alkyl -L-R ¹ is optionally substituted with halo 1, 2, 3, 4 or 5; R ² is halo; and R ^3a is H, C _{1 -3} alkyl and C _1-3 haloalkyl ) A compound of formula IIb1 or a pharmaceutically acceptable salt thereof:


(Wherein, -L-R ¹ is, halo, cycloalkyl, optionally substituted with substituents 1, 2, 3, 4 or 5 which are each independently selected from OH and CN, C _1-7 alkyl And R ² is halo or C ₁ haloalkyl ) A compound of formula IIIa below or a pharmaceutically acceptable salt thereof.


[Where:
-LR ¹ is C _3-7 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halo, cycloalkyl, OH and CN;
R ² is halo or C ₁ haloalkyl; and R ^3b is H, C _1-6 alkyl, C _1-6 haloalkyl, Cy ¹ , OR ^a , SR ^a , S (O) R ^b , S (O) ₂ Selected from R ^b and NR ^c R ^d , wherein said C _1-6 alkyl is Cy ¹ , C (O) NR ^c R ^d , C (O) OR ^a , halo, OR ^a , NR ^c R ^d , NR optionally substituted with ^{c C (O) NR c R} d and NR ^{c C} (O) 1,2 or 3 substituents selected from R ^b independently;
Cy ¹ and Cy ² are halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, — (L ^B ) _t1 -Cy ³ , CN, NO ₂ , OR ^a4. , SR ^a4 , C (O) R ^b4 , C (O) NR ^c4 R ^d4 , C (O) OR ^a4 , OC (O) R ^b4 , OC (O) NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 from ^{C (O) R b4, NR} c4 C (O) oR a4, S (O) R b4, S (O) NR c4 R d4, S (O) 2 R b4 , and _{^{S (O) 2 NR c4 R}} d4 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 independently selected substituents;
Cy ³ is halo, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, CN, NO ₂ , OR ^a6 , SR ^a6 , C (O) R ^b6 , C (O) NR ^c6 R ^d6 , C (O) OR ^a6 , OC (O) R ^b6 , OC (O) NR ^c6 R ^d6 , NR ^c6 R ^d6 , NR ^c6 C Independent from (O) R ^b6 , NR ^c6 C (O) OR ^a6 , S (O) R ^b6 , S (O) NR ^c6 R ^d6 , S (O) ₂ R ^b6 and S (O) ₂ NR ^c6 R ^d6 Independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from
R ^a is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1- 6} cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^b5 , OC ( ^{O) NR c5 R d5, NR} c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, S ( ^{O) NR c5 R d5, S} (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) 1, 2, 3, 4 or is selected from ₂ NR ^c5 R ^d5 are independently Optionally substituted with a substituent;
R ^a4 , R ^a5 and R ^a6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Independently selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cyclo Alkyl or heterocycloal Optionally substituted with a kill;
R ^b is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1- 6} cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^b5 , OC ( ^{O) NR c5 R d5, NR} c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, S ( ^{O) NR c5 R d5, S} (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) 1, 2, 3, 4 or is selected from ₂ NR ^c5 R ^d5 are independently Optionally substituted with a substituent;
R ^b4 , R ^b5 and R ^b6 are H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, Independently selected from heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, Heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, cyano, amino, halo, C _1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cyclo Alkyl or heterocycloal Optionally substituted with a kill;
R ^c and R ^d are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and Cy ² , wherein said C _1-6 alkyl, C 2 _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl is halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 cyanoalkyl, Cy ² , CN, NO ₂ , OR ^a5 , SR ^a5 , C (O) R ^b5 , C (O) NR ^c5 R ^d5 , C (O) OR ^a5 , OC (O) R ^{b5 , OC (O) NR c5 R} d5, NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5 ^{, S (O) NR c5 R} d5, S (O) 2 R b5, NR c5 S (O) 2 R b5 , and S (O) ₂ NR ^c5 is selected from R ^d5 are independently 1,2,3, Or optionally substituted with five substituents;
Or R ^c and R ^d together with the N atom to which they are attached, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _{1-6 ^{cyanoalkyl, Cy 2, CN, NO 2}} , OR a5, SR a5, C (O) R b5, C (O) NR c5 R d5, C (O) OR a5, OC (O) R b5, ^{OC (O) NR c5 R d5} , NR c5 R d5, NR c5 C (O) R b5, NR c5 C (O) NR c5 R d5, NR c5 C (O) OR a5, S (O) R b5, 1, 2 or 3 substituents independently selected from S (O) NR ^c5 R ^d5 , S (O) ₂ R ^b5 , NR ^c5 S (O) ₂ R ^b5 and S (O) ₂ NR ^c5 R ^d5 Forming a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted with
R ^c4 and R ^d4 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c4 and R ^d4 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c5 and R ^d5 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c5 and R ^d5 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
R ^c6 and R ^d6 are H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl , Independently selected from cycloalkylalkyl and heterocycloalkylalkyl, wherein said C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, Heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Cycloalkyl or heterocycle Optionally substituted alkyl;
Or R ^c6 and R ^d6 together with the N atom to which they are attached form a 4, 5, 6 or 7 membered heterocycloalkyl group;
L ^B is, OH, halo, -O- (C _1-4 alkyl), - O-with (C _1-4 haloalkyl), and 1, 2, 3, 4 or 5 substituents independently selected from amino Optionally substituted, C _1-4 alkylene; and
t1 is 0 or 1] -LR ¹ is C _2-6 alkyl optionally substituted with ¹ , 2, 3, 4 or 5 halo; R ² is halo; and R ^3b is H, C _1-3 alkyl and 32. A compound according to claim 31 or a pharmaceutically acceptable salt thereof selected from _C1-3 haloalkyl. 2. The compound of claim 1, selected from:
6-pentyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
6-butyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
6-butyl-3-methyl-8- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6-butyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6-butyl-3-methyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6-pentyl-6,9-dihydro-5H-tetrazolo [5,1-i] purin-5-one;
2-bromo-4-pentyl-8-phenyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-8-methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-pentyl-8-pyridin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-pentyl-8-pyridin-3-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
8-bromo-3-methyl-6-pentyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-Benzyl-2-bromo-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
8-bromo-6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
2-bromo-4-pentyl-8- (trifluoromethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
8-bromo-6-pentyl-3- (trifluoromethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-chloro-6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one trifluoroacetate;
2-chloro-8-methyl-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-chloro-4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one trifluoroacetate;
8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -2-bromo-4-butyl-1,4-dihydro-5H- [1,2,4] triazolo [ 5,1-i] purin-5-one;
8- [2- (3-Benzyl-1,2,4-oxadiazol-5-yl) ethyl] -4-butyl-2-chloro-1,4-dihydro-5H- [1,2,4] triazolo [ 5,1-i] purin-5-one;
2-Bromo-4-butyl-8-[(4-pyridin-4-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purine-5 -On trifluoroacetate;
4 ′-[(2-Bromo-4-butyl-5-oxo-4,5-dihydro-1H- [1,2,4] triazolo [5,1-i] purin-8-yl) methoxy] biphenyl- 3-carbonitrile;
2-Bromo-4-butyl-8-[(4-pyridin-3-ylphenoxy) methyl] -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purine-5 -On trifluoroacetate;
2-bromo-4-pentyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-butyl-8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-chloro-8-methyl-4-propyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-8-methyl-4-propyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
4-butyl-2-chloro-8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
8-bromo-6-pentyl-3-methyl-6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6-isobutyl-6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
5- (8-bromo-5-oxo-5H- [1,2,4] triazolo [3,4-i] purin-6 (7H) -yl) pentanenitrile;
8-bromo-6- (3,3,3-trifluoropropyl) -6,7-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6- (2-cyclohexylethyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
8-bromo-6- (3-methylbutyl) -6,9-dihydro-5H- [1,2,4] triazolo [3,4-i] purin-5-one;
2-Bromo-8-methyl-4- (4,4,4-trifluorobutyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one ;
2-Bromo-8-methyl-4- (5,5,5-trifluoropentyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one ;
2-Bromo-8-methyl-4- (3,3,3-trifluoropropyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one ;
2-bromo-4- (4-fluorobutyl) -8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4- (5-fluoropentyl) -8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4- (3-fluoropropyl) -8-methyl-1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
Bromo-4-butyl-8- (4-methoxyphenyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-butyl-8- (4-hydroxyphenyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-butyl-8- (4-methoxybenzyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
2-bromo-4-butyl-8- (4-hydroxybenzyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one; and 2-bromo -4-butyl-8- (methoxymethyl) -1,4-dihydro-5H- [1,2,4] triazolo [5,1-i] purin-5-one;
Or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition comprising a compound according to any one of claims 1-33 and at least one pharmaceutically acceptable carrier. 35. A composition for modulating HM74a receptor, comprising contacting said HM74a receptor with a compound according to any one of claims 1-34 . 36. The composition of claim 35 , wherein the adjustment is agonizing. 37. A pharmaceutical composition for the treatment of a disease in a patient, wherein the disease is associated with the HM74a receptor and comprises a therapeutically effective amount of a compound according to any one of claims 1-36 . . 38. The pharmaceutical composition of claim 37 , wherein the disease is associated with increased plasma FFA. The diseases include dyslipidemia, highly active antiretroviral therapy (HAART) -related lipodystrophy, insulin resistance, diabetes, metabolic syndrome, atherosclerosis, coronary heart disease, stroke, obesity, high body mass index (BMI) 39. The pharmaceutical composition according to claim 38 , which is increased abdominal circumference, nonalcoholic fatty liver disease, hepatic steatosis or hypertension.